Wait, you're OK? You're listening to Radiolab Radio from WNYC. Hey, Amjad, this is Radiolab. So last week we heard a story from Molly Webster was all about a new emerging disease, and this week we're actually going to go back to Molly.

Hello. Hi, there you are.

Yeah, I find because she has some new information about a story that she did a while back about beating back a disease, a disease that's been around for a while.

So we're talking about, well, sorry, you start.

No, we're talking about Gamma, which is interesting because Gamma was when you were gone.

Yeah. During your sabbatical. So here's the deal. It was 2016. I take a little break from the show just a few months. And Molly, along with Robert, decided to do something a little bit different on the show. She actually broke some news. She'd gotten a hot tip about some research that was just out from MIT and it was about Alzheimer's.

And I when I was there, they were in the midst of doing some really exciting follow up research that they had told me about off the record, but they weren't ready to talk about. But now they are ready to talk about it. OK, so here's what we're going to do.

We're going to play the original piece and then current day 20/20. Molly and Jad will pop in along the way with some updates. But for now, here is 2016. Molly with twenty sixteen, Robert.

Hi, I'm Robert Krulwich. I'm Molly Webster. This is Radiolab.

And today we've got breaking news. Robert Krulwich on break. This is something we've never done before, never done before.

Well, does anybody know about this yet? Well, it is a new bit of research. It's being published today. We've known about it for the last few months, but we haven't been able to talk about it until now.

What's this thing about? Oh, this is a discovery about Alzheimer's disease, which I think at this point is something that affects basically every family affected my family.

Yeah. And this is a discovery that is not a cure, but it's basically about looking at the brain, which is one of the most complicated things in the universe, I think, and poking at it in this super simple way and getting this bizarre result.

How bizarre. It's pretty. Pretty bizarre.

Hello. Hello. Hello. Hi, Molly. Hi, how are you? All right.

So last May I was talking to some folks over at the Brain Institute at MIT, and while I was on the phone with them, they started telling me about some research that hadn't been published yet.

So it was all very hush hush is pretty cool, though.

We ended up deciding to sign a non-disclosure agreement and it was based on the work of this woman, Liwei, Ty Liwei, tie, tie, tie, tie.

OK, I'm a professor and the director of the Peace Corps Institute for Learning a Memory at MIT.

Holy crap, you're a director. How do you have time to do? All I know that's a good question.

She is like a bad ass is what she is.

But this is a piece of work I'm very proud of and very excited about. So. OK, cool.

So I mean, so let me let me begin. OK, so historically people work on Alzheimer's, really focus.

So I would say generally when you talk to researchers about Alzheimer's disease, they either focus on an individual genetic factors, the genetics of the disease.

So the genes that predispose you maybe to Alzheimer's or the brain chemistry and Alzheimer's affects the chemicals in the brain, molecular pathological features.

But in my conversation with Liwei, she was talking about something totally different. We sort of look at it from a different angle. Her work all centers around something called the gamma frequency, the gamma gamma.

And what is I'm like it feels like something from Battlestar Galactica.

So I don't think it's that you could think of it as a particular beat. In your brain, a beat in the brain. Yeah, yeah, which means what exactly?

Well, just to oversimplify, one of the most complicated things in the known universe. OK, please do. You've got your brain. It's full of neurons, which are a certain type of brain cell.

We have billions of neurons in the brain. They have these long tentacles that are reaching out towards other neurons. And for the brain to function, neurons have to communicate with each other to process information. And the way they do that is they fire. Yes, an electrical signal will go through them in like zap another neuron and it'll turn it on and then into an electrical signal. We'll go through it and it'll zap another neuron and it'll turn it on.

But the cool thing is, is that when your brain is doing things like making you move or write a poem or think great thoughts, groups of neurons fire in sync all together on the same beat.

And there's a bunch of different beats that happen in the brain. Some of them are slow, like one beat per second. And that's when you're sleeping. If you're beating around 10 beats per second, like maybe you're sitting next to a campfire in an Adirondack chair or on like the totally other end of the spectrum, like some neurons fire at 600 feet per second. What are they doing that? I have no idea at all this is going on in your head simultaneously?

Yeah, no, that's the cool thing, is that when all of these beats in your brain come together, that's when you're able to process the world and understand it as it exists as human beings. Huh?

But getting back to our story, when your brain is doing something really tricky that requires super focused attention, working memory and so on, like trying to find your way home from the subway station or if you're in a new city, navigate around it.

There's a certain beat that sort of rises above the mall, and that is the so-called gamma frequency, this range between 30 beats per second, all the way up to one hundred beats per second. And this gamma frequency has been considered to be very important for the higher order cognitive function. And the interesting thing is that when you look at an Alzheimer's brain, what you see is there's actually less gamma happening or people say like the power of gamma is reduced.

Not all the neurons can be recruited to oscillate at the gamma frequency. It's still there. It's just quieter. It's like you turn the volume down, right? All right, so just to briefly sum up here, what we've got is a rhythm which we call Gamma, which is used when we have complicated or higher thoughts in the brain, which when you got Alzheimer's, kind of gets saggy or tired.

Yeah, yeah, totally. And of course, obviously in an Alzheimer's brain, there's a lot going on. And this is just one of the things, right?

You've got the plaques that build up around the neurons, the stuff that sucks up your brain and makes it hard to.

Yeah, yeah, totally. It's like cobwebs in the brain. And then the connections between neurons gets all muddied and immune cells get messed up.

Alleyway time is like. Forget all that, what would happen if I just bring the Gammer back? Yeah. We decided to just manipulate gamma oscillations. How do you how do you do that? Well, hello, hello, hello. Technology, hi, this is Molly. Hi. Hi, hi. Technology you can find at the Massachusetts Institute of Technology and actually I went and took a train up to Boston to MIT not too long ago walking into the Picower Institute.

It's a big, shiny glass building. Why eventually Lutie came striding into her office to meet me.

My understanding is that you want to see some of the experimental setup. And so Liwei led me down the hall to this tiny room.

The mice just entered the room, brought in these adorable little mice.

Oh, my gosh. They're like little black and soft and furry.

Their ears are tagged with little metal tag on this.

OK, so. So here's what they did. They get some ice.

We started off with a mouse model, not the mice I actually got all excited over.

But mice that have an early stage of Alzheimer's disease was multiple notable defects. Do they have the gunky stuff in them yet or is that later?

No, but they do have elevated levels of of beta amyloid peptides, which is this protein that forms the plaques.

So it's like basically pre plaque gunk. But the important thing to waitI in our team is that they have less gamma going on in their brains.

If you remember, the whole plan here is to bring the gamma back. Yes.

So to do that, they get what might be the world's tiniest drill and they drill a small hole into the skull of the mouse. And then they take a really thin fibre optic cable. They slide it through the hole into the brain, and then they get this laser of blue light to flicker at 40 beats per second gamma frequency.

And they turn that on in the light, travels down the fiber optic cable deep down into the brain to this group of cells that they've modified in the hippocampus to be sensitive to light. So when this pulsing light hit these cells, they actually began to fire at 40 beats per second at gamma frequency. And they would keep these cells firing at Gamma for one hour, firing and firing and firing and firing and firing.

And then after one hour, they turn off the light. And then eventually they started looking at the the brains of these mice trying to figure out if anything was different after the light flashed.

And they see to our march surprise, we're not expecting this at all.

We found after they shot this pulsing light into the brain, there was suddenly nearly half as much of that, soon to be nasty black gunk stuff that was filling up their hippocampus. Half of the yeah, half half of the stuff was just swept away.

Yes, 40 to 50 percent reduction of beta amyloid.

That's just seems crazy. This is crazy.

I mean, we were just so surprised to they know why the fluid so turned out, the pulsing lights somehow triggered the brain's cleanup crew. Microglia these cells in the brain that are called microglia. You can say they're the generators of the brain.

And in a normal brain, these janitor cells usually gobble up the gunk.

But in Alzheimer's disease, it's known that microglia the they they don't sort of function normally anymore.

It's like these janitors just sort of stop cleaning up and go on strike.

There we go. OK, cool. OK, so we're looking at a screen that's now flat. It's not not when I was at MIT, one of Levey's grad students.

My name is Anthony Martorell, a second year was showing me side by side comparisons of these mice brains on the screen.

Can you guess what that is? Which part? The green things. Microglia.

Yeah. Yeah.

And you see after one hour of gamma. Wow. So that the microglia, the cell seems a lot bigger clearly see these round bodies.

Yeah.

And also Dubberly seems to have more amyloid. Oh. Like they're doing more eating. Yes. They go back to eat more amyloid again. It's like somehow making the neurons fire turned on the sanitation system in the brain.

But but the most the wild results. Wait, there's more wild. Oh my gosh. You got to hear this because what I'm about to tell you, you may say, no, I don't believe it. It's science fiction.

OK, so so one of the things Liwei and her team were starting to think was that drilling in fiber optic cable is very invasive. Right. You'd never be able to do that on a human. Exactly. So we started to say, well, what if we can get the light into the brain in a different way? Like maybe we could go through the eyes to the hole in your head would be your eyes instead of a hole in your head.

Yes. So Liwei and her team created what I like to think of as the Flicker Room. This is the room.

This is a room. And it turns out I learned upon my visit it is just a storage closet.

You know, you have a it's just like a plastic table, very DIY. Yeah, it's a it's a plastic table, you can buy a target, there were some plastic shoebox size containers lined up on the table for the mice and then you'll see the strip around the edge of the table.

Basically surrounding all the cages are duct tape, strips of LED lights.

And the reason why we use LEDs is because of regular light bulb. It can flash fast enough.

And so the idea is, what if we just put the mice in this room and just let the light flicker at 40 beats per second?

So you want to show Marley like a turn? Yeah. And so we turn off the overhead light in the room. So it's very black and then. Oh, wow, the room was now glowing with this white led light. So the light is turning on enough 40 times a second. It's so there's you know, you don't see anything going like on or off. It just looks like something's on. But it kind of feels like my eye is twitching.

And so it's blurring the the blurring the light a little. Just on the edges, though, just on the edges.

And so they put mice in this room for an hour and just let them kind of bathe, bathe in this in this glow.

And guess what? What we look at the amyloid beta levels in the visual cortex, and we found there is a 50 percent reduction, 50 percent, 50 percent shining light in their eyeball.

Yes, we think they did.

They didn't do any drilling in our schools or anything. So they didn't drill. They didn't tweak the mouse brain cells to be sensitive to light. They just filled the room with occasional LEDs flashing at a particular frequency for an hour.

Now, do you see how are you going to tell me? I don't believe it is science fiction. And they follow this study up with another study, which was done in the same way or the same flicker room light through the eyeballs. And only this time they put the mice in there for one hour a day for seven days, and they took mice that had full blown Alzheimer's. So this is like cognitive decline. They're forgetting things and they've got heart and plaques in their brain and they see the same thing.

Nearly half of the stuff was cleared away. Wow. Half or.

It's just flickering light in front of the mice. That's the shot. I mean, that's the shocking thing. The thing I didn't understand after talking to you about your study was I was like, why hasn't everyone done this before? Like, why didn't everyone go? We should just shine light through eyes, see?

Well, you know, that's really the most unexpected and exciting aspect of our study, which is something this simple. Yet, you know, it has never been done before.

You know that one of the things one of the caveats here is that if you don't do the flicker light room every twenty four hours, the level of gunk in the brain starts going back up again. And so now they're trying to figure out how they can keep those levels down, maybe even for good.

OK, current DayJet here, we'll come back to the original story in a bit and to a big question that all of this work raises.

But first, a little update 20/20. Molly recently called Liwei tie again. Hello. Hello.

Hello, Molly.

To see what she has been up to since that original research. How are you? I'm doing great. Yeah. So much new things coming up. And I'm just excited all the time.

And so, as I said when I was there in 2016, we had talked a bit off the record. And since then, Liwei Tie has published papers gone on the record. And what we were talking about is that they were looking to expand their sensory toolkit. So instead of using gamma light, they did gamma sound.

What what what made you pick sound? So we know that we can see. We can hear. We can taste, we can smell, we can touch. And among all of this, we figure that the sound is relatively straightforward to produce a 40 hertz gamma sound.

Oh, interesting. So instead of shining a light in there in the subject's eyes, they would play a tone or something and it would have the same effect. Yeah.

So they just built a sound that has that same gamma frequency built into it, like the lights in the Flicker room and then they play it for the mice. Yeah. What is the equivalent of like the sound flicker room?

We basically just, you know, add, you know, loud speakers. So the sound comes in through the mouse ears. Right. So there are sensory nerve cells like the waves come in, it gets converted to an electrical signal. This electrical signals then can be transmitted across the brain circuits.

So what do we know what it sounds like? I have it here.

Oh, so I'm going to hit play and then you tell me if you can hear it. Okay. Oh, my God. It's kind of a crazy sound. I don't want to hit play. OK, three, two, one.

Oh, God. Yeah. Wow. Yeah. It's like a little insect boring into my brain. There's like a subbase in there that's making my stomach like. Oh right.

I the first time I heard it I like ripped my headphones off my head and then I then really converted and found it super soothing.

I'm not there yet.

OK, it's I think we should probably also do the caveat of like there could be some way in which this comes through your headsets. In a weird way, it depends on where the speaker is said, yada, yada, yada, where this is not the sound. Yes, in a way that they are hoping and maybe we didn't want to take it a step further and say do not use the. Yes, please do not use this sound at home to self treat.

They were playing this for mice, though. When they were playing it for mice. We were able to see very similar beneficial effects as those exposed to 40 hertz gamma light.

They see like the what we talked about in the first episode, which were the microglia, which she calls like the the trash picker uppers of the brain ages, you know, completely surrounding the amyloid plaques.

And so they start eating all that stuff up. After one to two weeks of exposure, we saw about 30 to 40 percent reduction of the amyloid plaques. Wow.

So listening to that sound that you just played, just listening to it is a kind of. Cleansing brain therapy of a kind. I mean, yes, for mice right now. Yes, man, the interesting thing is, is they as of yet still have no idea why all this is happening, why microglia seem to eat more of the trash. They have no idea.

But they must have some some theory, right or. No, no, no.

And she's done these studies that other rhythms like 40, 100, 42 herds with thirty eight herds, you know, they've tried 80 and they've tried 20.

And for some reason, 40 is the sweet spot where you see this activity and you don't see it in other places. But beyond, though, why like why is it 40 or why does Gammer do this and nothing else? Does this or other things like Gamma don't do this? All the new stuff with sound actually leads us to the same question we had in the original episode.

The the big question, which Robert put to me, if the mouse no longer has quite as much junk in its head, does that mean that it can remember things that happened to it, that it gets work? Yeah, that is their big next research. That's what they know. They don't know. That's what they're to. That is now the next step. But nobody really understands how plaques and the gunk build up in the brain relates to memory and cognition.

And the dogma in the field is that when you have Alzheimer's, you can't form new memories. And once you lose a memory, it's gone for good. But there is another group at MIT that is actually sort of challenging that assumption that you can never get a memory back because the patient could never tell us.

We all assume that the information had to be gone. Oh, really?

Yeah. And we'll get to them. But first, we have to go to a break.

And of course, we'll be back with more updates right after this.

Hi, my name is Rachel Melisma and I'm calling from Alice Springs, Northern Territory, Australia. Radiolab is supported in part by the Alfred P. Sloan Foundation, enhancing public understanding of science and technology in the modern world.

For more information about Sloan at Sloan Dog Science reporting on Radio Lab is supported in part by Science. Sandbox is Science Foundation initiative dedicated to engaging everyone with the process of science.

Hey, Chad, here we are back, looking back at Molly Webster's piece from 2016, peppering in some updates as we go. We're going to keep rolling here with the original for a bit and then we'll get more from current day twenty. Molly and me in a little bit. I'm Robert Krulwich.

I'm Molly Webster. This is Radiolab. And we're back.

And just before the break, you said that there may be a way to bring a memory back from the Alzheimer's to pull the memory back into into place.

Yeah. Why why are we so quick to jump to the conclusion that the information was somehow completely gone?

And the person who said that to me is this guy, I'm directorially.

I'm a fourth year graduate student in the summer, Angola, over at the Tanigawa lab, they were thinking, what if we could figure out exactly where the memory should be in the brain and just give that spot a little bit of juice.

Right.

So they took some mice that were just starting to lose their ability to remember things. And they thought, OK, let's try to give them a memory.

We put them in a box of has a particular smell, some sort of lighting and some texture on their feet, a little mouse carpet or. That's exactly what we really. Yeah, OK. I think it's got to the point is the box looks and feels and smells different than any other box they would hang out in.

And then you give them a light electrical shock and the mice, they just freeze, they don't move at all, which is a sign that they're afraid.

They hate the box. And for the rest of the afternoon, which is very long time and mouse time, they go on hating the box, which means with the carpet in the light and the smell, if you put it back in there, it'll freeze because it remembers the shock.

Yes, but a day or a week later, when the same mice were put back into the same box, instead of being scared of the box, they would just continue investigating as if nothing happened. They could not remember.

So Dhiraj and his team did what Liwei did.

They got some modified mice and then they put a little hole in their head. They slid in a fiber optic cable.

They shine some light to trigger the neurons that they think hold this memory. And they were in a fear section near the fear section. So leading on the path to the fear section. So we do this and then put them back into the box, the box with the particular lighting and smell and carpet and ask, is there any change in their behavior?

Will they act afraid again? Do they show any more memory?

And they did. Wait, shut up. They actually were scared of the box again. Exactly. They showed recovered memory. Wow. Oh. So that's like, bam, that memories in there exactly. Behaviourism. You can dig up the memory by shining light in the right place.

Yeah, I was always under the impression that the memories were totally lost, right.

I think that's not just you. I think that's essentially the entire field, what you described just because. And that's good, because the patient could never tell us. We all assumed the information had to be gone.

So one of the things to say is that Dhiraj did tell me that, you know, all of the experiments they did are in mice that have early Alzheimer's.

The thought is, though, is that once you get to the late stage of the disease, there's enough damage in the brain that you really wouldn't be able to get those memories back.

That might be right, that a memory loss is just lost. But, you know, when you when you have someone in your house and you and you live with this disease day in and day out, the disease just goes its own way and it can puzzle you or frighten you or suddenly declare something new that you didn't expect. So, for example, my dad had it for about 19 years. It was a slow act of disappearing that he did.

Where I mean, the last time my father came to was so far into the disease. He hadn't spoken for a year and a half. He was sitting at the table for the Passover Seder.

And there's a song that you sing, but it goes Die, die, die, die, die, die, die, die. So it's just a chorus. And from out of nowhere, this.

Being at the end of the table, who I knew was my father, who hadn't spoken in a year and a half or two and had not spoken coherently for three, suddenly flew into the song.

And sang the song, a full throated lay at the table like. The reappearance of some just last figment of himself. And it was it was both horrifying and extraordinary. But, you know. I think that the fact that maybe some information still persists. Hopefully someday we could. With something we could do, um, but yeah, this is all in my mind at the moment. As long as we can figure out how to rebuild the pathway to retrieve the memory, then I think there is hope.

And then I want to jump in here with one more part of the sound update, which is that Liwei and her team in particular are thinking about it in regard to capturing memories, because where this research probably gets even more interesting is when you do the light flashing and that sound at the same time, we eventually just decided, why don't we, you know, put the two together and see how the animals respond.

This is becoming like a Misbah Nahar. And when they did that, they saw this gamma beat in the brain, but not just in the auditory cortex or the visual cortex, not just in one particular brain region. We are seeing across different brain regions. So the hippocampus got involved in that prefrontal cortex, got involved, and then there was the neocortex and maybe even the parietal lobes.

So there was like activity like all across the brain is a little bit like a like a whole bunch of like, clocks coming into.

Yeah, yeah. Yeah. And imagine thinking it's only going to affect one clock, but it actually somehow pulls them all into synchrony. Again, they saw the microglia doing their cleanup thing all across the brain. But most coulis they also saw just like almost like a rebuilding of neuronal circuitry. So like the synapses between neurons seem to improve.

Then basically this repaired the disrupted neuropsychiatry. And I think this in turn can lead to recovery of learning, of memory.

And what she's been finding with mice is that it seems to basically, in a way, she's done something very similar to a Dhiraj has done, but with her own light and sound technique. And the memories came back.

That's so interesting.

And the mice, so very impressive improvement to the cognitive ability.

So it's almost like two things happening, which is you're seeing physiological effects in the brain and then you're seeing the layer on top of that, which is then the memories that live in the physiology are also having some impact.

Yes. So with all the stuff, Supernus, you feel like it's caveat time. And for the caveat, I am going to throw back to the caveat we had in the original piece.

You know, I I personally think the most important question is whether humans respond similarly. I mean, keep in mind that both Dhiraj study and Liwei Ties are in mice, not humans.

Right.

So I know you have a thought that like why like is there a reason that a human neuron might react differently than a mouse?

The thing is, I think especially in Alzheimer's field, I mean, people got burned a lot.

You know, there's like a ninety nine point six percent failure rate in moving something that seemed to work in mice to humans in Alzheimer's six.

Yeah, yeah. That was a study that came out in 2012. That's a horrible number.

So I just got to be really conservative. I look back, I'll dial it back, you know, while we have in mice just just so exciting and so unexpected, so much fun. But, you know, I'm going to keep my mind open when it comes to humans.

The plan is, is that we're going to find out because they're going straight to humans. Oh, they're going to do human trials. Will they want to. So, yeah, I guess we'll see. And so we have my final final update, which is that Liwei Tie and her crew have indeed started human trials.

So we indeed managed to get a oraibi approved for our first very small scale study in early stage Alzheimer's disease subjects.

They're doing a clinical trial with 15 Alzheimer's patients.

How far how far into the study are they? I talked to Leeway in January and they had some people enrolled. So we have recruited whiffing individual people. We basically installed our light and sound device in home.

Really? Yeah.

So they themselves or their caregiver can turn on the device and then they sit there and they get the light flashed in their eyes and they get the sound flashed at their ears and they're doing it an hour a day for six to eight months, maybe six to nine months. And and they're just collecting data. And and I guess we're going to see, you know, we are talking about living, human being.

It's not that we can just pick out a brain and see the microglia or.

All of this, but we are evaluating all of the subjects in terms of their cognitive ability, and we also do MRI scan to look at how active their brain activity is.

And do you have any. Any intel on what they're seeing so far? I wish I mean, every step of the way, to be quite honest, it's always a surprise.

It's like, oh yeah, this can do you know, Gamma can do this on Gamma can do that. You know, I think the journey, it's like a magic carpet ride.

This is the glorious part of all this, this organ of ours, the brain is so crazily complicated with like whatever 100 trillion connections or whatever it is, there's so much chance there's going to be a lot of surprise.

Yeah, it's like almost even if it doesn't lead to any treatment in humans or something super concrete, it's like we know this little secret about the brain now and there's something that feels like beautiful in that.

Yeah, I'm actually setting this up for my Christmas tree. Are you really? Yes. Yeah, we I just bought the new red lights and they can they can flicker a different color with different colors so each individual bulb can travel through colors. But while they're doing that, they're going to be flickering at 40.

We're going to have a very therapeutic Christmas in in the Lutie household.

This is the tree in your home?

Oh, yes. Yes.

And I want to have an eggnog next to that tree. Yeah.

And this year, you might even add some 40 gammer jingle bells whoknows. Wow. And that's the thing.

Yeah. Thank you. Thank you, Molly. Obviously, this update was reported by Molly Webster and it was produced by Rachel Kucik and of course, don't say this enough. Big props to Sean Wheeler. Special thanks to Dhiraj Roy.

I am Jad Abumrad, just a man who longs for the 40 kilohertz coming home of the gamma. I shall go and listen to that sound now. In the meantime, thank you for listening. See you next week. See? I was just calling from Bristol in the UK, Radiolab is created by Jadwin Roche with Robert Krulwich and produced by Someone Winter dealing with our director of sound design. Susie Lichtenberg is our executive producer of Dancing with Simon. Jeremy, bring back a Bresler.

Rachel Piecyk David Gabble Happy Tracy. Let's not give the Tobin no any love if nothing. Sarah Quarrie, Mark Waters and Wendy Webster with help from Shinola. There are some but Greg check it is Michelle. She tells me when she tells me she wants.