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INTRO: Wait, you’re listening, OK, Alright, OK, Alright. You’re listening to Radiolab. From WNYC.
RK: Hi, I’m Robert Krulwich
MW: I’m Molly Webster
RK: This is Radiolab, and today.
MW: We’ve got breaking news Robert Krulwich
RK: Break--this is something we’ve never done before
MW: Never done before
RK: Does anybody know about this yet?
MW: Well it is a new bit of research that’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
RK: What’s this thing about?
MW: Oh it’s--this is a discovery about Alzheimer's disease.
RK: Uh hu
MW: Which is at this point I think something that affects basically every family.
RK: Affected my family, yeah
MW: And this is a discovery that is not a cure but it’s basically about looking at the brain, whi9ch 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.
RK: How bizarre?
MW: It’s pretty, pretty bizarre
MW: Hello hello?
LT: Hi Molly.
LT: Hi how are you?
Alright. So last May I was talking to some folks over at the Brain Institute with 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. It was pretty cool though. We ended up deciding to sign a non disclosure agreement, and it was based on the work of this woman, Li-Huei Tsai
LT: Li-Huei Tsai
MW: Tsai, OK
LT: I’m a professor and the director of the Picower Institute for learning and memory at
MW: Holy crap you’re the director. How do you have time to do all of that?
LT: I know, that’s a good question.
She was like a badass is what she is
LT: But this is a piece of work I’m very proud of, I’m very excited about.
MW: OK cool, so--
LT: So let me, let me begin. So, historically, people work on Alzheimer’s, really focused--
So, I would say generally when you talk to researchers about Alzheimer’s disease, they either focus on
LT: On individual genetic factors
The genetics of the disease, so the genes that predispose you maybe to Alzheimer’s
The brain chemistry and how Alzheimer’s affects like chemicals in the brain
LT: Molecular pathological features
But in my conversation with Li-Huai, she was talking about something totally different
LT: We sort of look at it from a different angle
Her work all centers around something called
LT: The gamma frequency
RK: The gamma freq--
LT: Mhm. Gamma.
MW: And what is gamma? It feels like something from Battlestar Galactica
MW: So I don’t think it’s that
LT: So this gamma, so called gamma--
You could think of it as a particular beat. In your brain
RK: A beat in the brain?
RK: Which means what exactly?
MW: Well, just to oversimplify one of the most complicated things in the known universe,
RK: OK, please do
MW: You’ve got your brain. It’s full of neurons, which are a certain type of brain cell
LT: We have billions of neurons in the brain
They have these long tentacles that are reaching out towards other neurons.
LT: and for the brain to function, neurons have to communicate with each other to
And the way they do that is, they fire
An electrical signal will go through them and it will like ZAP another neuron and it will turn it on and then like an electrical signal will go through it and it will zap another neuron and it will turn it one
But the cool thing is that when your brain is doing things like making you move or write a poem or think great thoughts, groups of neurons
LT: 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 ten 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 like 600 beats per second
RK: What are they doing?
MW: I have no idea, I just--
RK: And all of this is going on in your head simultaneously?
MW: Yeah 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
MW: But, getting back to our story, when your brain is doing something really tricky that requires super focused
LT: Attention, working memory and so on
You’re like trying to find your way home from the subway station or you’re in a new city navigate around it, there’s a certain beat that sort of rises above them all. And that is
LT: The so-called gamma frequency
This range between 30 beats per second all the way up to 100 beats per second
LT: 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 the power of gamma is reduced.
LT: 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
RK: Alright, so just to briefly sum up here what we’ve got is a rhythm which we call gamma
RK: Which is used when we have complicated or higher thoughts in the brain. Which when you got Alzheimer’s, kinda gets saggy or tired or vanishes
MW: 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
RK: The stuff that gucks up your brain and makes it hard to think
MW: Yeah yeah yeah. Totally. It’s like cobwebs in the brain. And then the connection between neurons gets all muddied, and immune cells get messed up.
But Li-Huei Tsai was like, forget all that. What would happen if I just bring the gamma back?
LT Yeah. We decided to just manipulate gamma oscillations.
RK: And how do you do that?
MW: [blows] hello hello hello?
MW: 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
MW: we’re walking into the Picower Institute
Big shiny glass building.
LT: Molly hey, nice to meet you
Eventually Li-Huei Tsai came striding into her office to meet me
LT: My understanding is that you want to see some of the experimental setup
And so Li-Huai led me down the hall to this tiny room
MW: Ooooh. The mice just entered the room.
Brought in these adorable little mice
MW: Oh my gosh they’re like little black and soft and furry
MW: Their ears are tagged, there’s a little metal tag on them
LT: OK, so--
So here’s what they did. They get some mice.
LT: 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.
LT: With multiple notable defects
RK: Do they have the gunky plaque stuff in them yet or is that later?
MW: No, but they do have
LT: Elevated levels of, of beta analoidpeptides.
Which is this protein that forms the plaques
So it’s like basically pre-plaque gunk. But the important thing to Li-Huei Tsai and her 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
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 and into the brain, and then they get this laser of blue light
LT: To flicker
At 40 beats per second
LT: Gamma frequency
And they turn that on the and the light travels down the fibre optic cable, deep down into the brain to this group of cells that they’ve modified
LT: In a hippocampus
To be sensitive to light. So when this pulsing light hit these cells, they actually began to fire at 40 beats per second
LT: At gamma frequency
And they would keep these cells firing gamam
LT: For one hour
Firing and firing and firing and firing
LT: And then, after one hour
They turn off the light and then eventually they started looking at the brains of these mice
Trying to figure out if anything was different
MW: After the light flashed. And they see
LT: To our much surprise
They were not expecting this at all
LT: We found
After they shot this pulsing light into the brain there was suddenly nearly half as much of that soon to be nasty plaque gunk stuff that was filling up their hippocampus
RK: A half of the--half?
MW: Yeah. Half of the stuff was just swept away
LT: Yes. 40 to 50 percent reduction of beta amyloid.
MW: That just seems crazy
LT: this is crazy, I mean, we were just so surprised
RK: Do they know why the flood of light would--
LT: Turn out
The pulsing light somehow triggered the brain’s clean up crew
These cells in the brain that are called microglia
LT: You can say they’re the janitors of the brain
And in a normal brain, these janitor cells usually gobble up the gunk.
LT: But in Alzheimer’s disease, it’s know that microglia they don’t sort of function normally anymore
It’s like these janitors just sort of
LT: Stop cleaning up
And go on strike
AM: There we go. OK cool
MW: So we’re looking at a screen that’s now flat. It’s not--
When I was at MIT, one of Li-Huai grad students
My name is Anthony Marcherell, second year
Was showing me side by side comparisons of these mice brains on the screen
AM: Can you guess what that is?
MW: Which part?
AM: The green things
AM: Microglia, yeah
And you see
LT: After one hour of gamma
MW: Wow so--
LT: The microglia, the cell seems a lot bigger
MW: You can clearly see these round bodies.
LT: And also the body seems to have more amyloids.
MW: Oh, like they’re doing more eating
LT: Yes. They go back to eat more amyloids again
It’s like somehow making the neuron’s fire turn down the sanitation system in the brain
LT: But, but the most wild results--
MW: Wait, there’s more wild?
LT: Oh my god you gotta hear this, because--what I’m about to tell you, you may say, no
I don’t believe it. It’s science fiction
LT: OK. So--
One of the things Li-Huei and her team was starting to think was that drilling and fibre optic cable
LT: Is very invasive, right
You’d never be able to do that on a human
LT: 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
RK: So then the hole in your head would be your eyes instead of a hole in your head?
So Li-Huei and her team created what I like to think of as the flicker room
MW: Wait is this the room?
LT: This is the room
It turns out, I learned upon my visit, it is just a storage closet
MW: You know, you have a--what is this, just like a plastic table
AM: Yeah, it’s a plastic table you can buy at Target
There were some plastic shoebox-sized containers lined up on the table for the mice, and then
LT: Do you see this strip?
Around the edge of the table
LT: Basically surrounding all the cages
Are duct-taped strips of LED lights
AM: And the reason why we use LEDs is because of a regular lightbulb, it can’t flash fast
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
LT: So you want to show Molly like I’ll turn this on--
And so we turn off the overhead light in the room so it’s very black. And then
MW: Oh wow
The room was now glowing with this white LED light
AM: OK so the light is turning on and off 40 times a second
MW: It’s--so you don’t see anything going like on or off, it just looks like something is on
but it kinda feels like my eye it twitching
MW: And so it’s blurring, it’s blurring the light a little. Just on the edges though.
LT: Just on the edges
And so they put mice in this room for an hour and just let them kinda bathe in this glow
LT: And guess what?
LT: We look at the amyloid beta levels
LT: In the ventral cortex, and we found there is a 50 percent reduction.
MW: 50 percent?
LT: 50 percent reduction
MW: Just from shining light in their eyeballs?
RK: Wait a second. They didn't--they didn’t do any drilling in their skulls or anything?
MW: No, they didn’t drill, they didn’t tweak the mouse's’ brain cells to be sensitive to light this is just--
RK: They just filled the room with occasional LEDs flashing at a particular frequency
MW: For an hour.
LT: Now do you see--are you gonna doubt me? I don’t believe it, it’s science fiction?
And they followed this study up with another study which was done in the same way sort of 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 hardened plaques in their brain. And the see the same thing. Nearly half of the stuff was cleared away
LT: It’s just flickering light in front of the mice.
MW: That’s the shock--I mean that’s the shocking thing. The thing i didn’t understand
after talking to you about your study is I was like, why hasn’t everyone done this before? Like why didn’t everyone go, we should just shine lights through eyes
LT: See, well you know, that’s really the most unexpected and exciting aspect of our
study, which is, something this simple yet it has never been done before
LT: You know, that--
One of the things, one of the caveats here, is that if you don’t do the flicker light room every 24 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
RK: 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, it gets mentally more acute?
That is their big next research
RK: SO they don’t know
MW: they don’t know, that’s what they’re--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.
MW: But there is another group at MIT that is actually sort of challenging that assumption that you can never get a memory back
DR: Because the patient could never tell us, we all assumed the information had to be
RK: Oh really
MW: yeha. And we'll get to them, but first we have to go to a break
This is Kevin Murray from Ft. Collins Colorado, Radiolab is supported in part by the Alfred P. Sloan Foundation, enhancing public understanding of science and technology in the modern world. More information about Sloan at www.sloan.org
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RK: I’m Robert Krulwich
MW: I’m Molly Webster
RK: This is Radiolab
MW: And we’re back
RK: And just before the break, you said that there may be a way to bring a memory back from the Alzheimer’s disease, to pull the memory back into place
DR: Why are we so quick to jump to the conclusion that the information was somehow
And the person who said that to me, is this guy
DR: I’m Dheeraj Roy, i’m a fourth year graduate student in the Susumu Tonegawa Lab
Over at the Tonegawa 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
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.
DR: We put them in a box that has a particular smell, some sort of lighting, and some
texture on their feet
MW: A little mouse carpet, or--
DR: That’s exactly what it is
MW: Wait, really?
MW: OK, mice on carpets, got it.
The point is, the box looks and feels and smells different than any other box they would hang out in
DR: And then you give them a light electrical shock
And the mice--they just freeze
DR: They don’t move at all
Which is a sign that they’re afraid.
DR: They hate the box
And for the rest of the afternoon, which is a very long time in mouse time, they go on hating the box, which means with the carpet and light and the smell
MW: If you put it back in there, it will freeze, because it remembers the shock
DR: A day or a week later
When these same mice are put back into the same box, instead of being scared of the box, they were just continuing investigating as if nothing happened. They could not remember
So Dheeraj and his team did what Li-Huei did. They got some modified mice and then they put a little hole in their head, they slid in a fibre optic cable, they shined in some light to trigger the neurons that they think hold this memory
And they were--
RK: In the fear section
MW: Near the fear section. So leading on the path to the fear section
DR: So we do this
DR: Put them back into the box
The box with the particular lighting and smell and carpet
DR: And ask, is there any change in their behavior?
Will the act afraid again?
DR: Do they show any more memory? And they did
MW: Wait. Shut up, they actually were scare of the box again?
DR: Exactly. They showed recovered memory
MW: So that’s like, bam, that memory’s in there
DR: Exactly. Wah-lah, the behavior is back
RK: You can dig up the memory by shining light in the right place?
MW: I was always under the impression that the memories were totally lost.
DR: Right. So I think that’s not just you. I think that’s essentially the entire field what you
described, just because, because the patient could never tell us, we all assumed the information had to be gone
MW: So, one of the things to say is that Dheeraj 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
RK: That might be right. That a memory lost is just lost. But you know, when you, when you have someone in your house and you, and you live with this disease
RK: day in and sday out, the disease just goes it’s 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 nine, ten years. It was a slow act of disappearing he did, where I mean the last time my father came to
RK: 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, and it goes [singing] 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
RK: Suddenly flew into the song and sang the song full throatedly at the table. Like the reappearance of some just last figment of himself. And it was, it was both horrifying and extraordinary. Both, you know
DR: I mean I think that’s the fact that maybe some informations still persists, hopefully
someday we can still kinda maybe there’s something we can do. But yeah. This is all a--in my mind at the moment.
LT: as long as we can figure out how to rebutte the pathway to retrieve the memory, then
I think there is hope.
MW: This is Li-Huei Tsai again
LT: But you know, I personally think the most important question is whether humans
I mean, keep in mind that both Dheeraj’s study and Li-Huei Tsai’s are in mice, not humans
LT: Right, so I--
MW: And do you have a thought, that like, why, like--is there a reason that a human
neuron might react differently than a mouse?
LT: The thing is, I think especially you know in Alzheimer’s field, I mean people got
burned a lot. Just so many--
You know, there’s like a 99.6 percent failure rate in moving something that something that seemed to work in mice to human in Alzheimer’s
MW: Yeah yeah. That was a study that came out in 2012
RK: That’s a horrible number
LT: So I just gotta be really conservative here
MW: I’ll dial it back, I’ll dial it back
LT: You know, what we have in mice, it just, is just so exciting and so unexpected and so
much fun, um, but you know, I’m gonna keep my mind open
LT: When it comes to humans
The plan is that we’re gonna find out because they’re going straight to humans
RK: Oh. They’re gonna do human trials?
MW: Well they want to, so yeah, I guess we’ll see
RK: This is the glorious part of all this. This organ of ours, the brain, is so crazily complicated with like whatever, a hundred trillion connections or whatever it is. There’s so much chance there’s gonna be a lot of surprise
MW: Yeah. It’s like almost even if it doesn’t lead to any, a treatment in humans or something super concrete
MW: It’s like we know this little secret about the brain now, and there’s something that feels like beautiful in that
LT: Yeah, I’m actually setting this up for my Christmas tree
MW: Are you really?
LT: Yes--we--I just bought the new LED lights and they can, they can flicker a different
color, with different colors
MW: Oh, so each individual bulb can travel through colors but while they’re doing that,
they’re gonna be flickering at 40.
LT: We’re gonna have a very therapeutic Christmas
MW: In the Li-Huei Tsai household. This is the tree in your home.
LT: Yes, yes
MW: I want to have an eggnog next to that tree
RK: Yeah. Well thank you Molly for what a remarkable story that was, um
MW: You’re welcome
RK: It was also produced by Annie McEwen, Matt Kielty, Molly Webster again, with help from Simon Adler and special thanks to Susumu Tonegawa at MIT. And thank you all for listening
This is Tiana Briton calling from LA. Radiolab is produced by Jad Abumrad, Dylan Keith is our director of sound design, Soren Wheeler is senior editor, Jim York is our senior producer. Our staff includes Simon Adler, Benna Farrell, Dana Gabel, Matt Kielty, Robert Krulwich, Annie McEwen, Latif Nasser, Melissa O'Donnell, Arienne Wack, and Molly Webster. With help from Tracie Hunt, Ngar Fatali, Phoebe Wang, Katie Ferguson, Alexander Lee Young, W. Harry Fortuna, and Persea Verlin. Our fact checkers are Eva Dasher and Michelle Harris.