SPEAKER_05 0:00

Just for carbon nanotubes, uh, a very good use case for them is the fact that they're fluorescent. Uh and not only are they fluorescent, but they're fluorescent in the near-infrared region.

SPEAKER_08 0:09

So This is okay, this is super cool. Wait. Okay.

SPEAKER_05 0:12

So did you shine light on them? Yeah, yeah. Uh and then they so you excite them with one wavelength and then they emit in another. But um and we do that all the time.

SPEAKER_11 0:20

I gotta ask you, I'm sorry, I gotta ask you a question. How many carbon molecules is the circumference of the tube?

SPEAKER_00 0:27

I'd have to draw it out. It's gonna wild.

SPEAKER_11 0:29

Oh, we got it. Let's do it. We got it. We got a whiteboard right here. Um But it's but like is it like six, twelve, twenty-five.

SPEAKER_05 0:37

Um so it's a graphitic lattice, so they're benzene rings.

SPEAKER_11 0:40

Okay. Um benzene is just five, right? Or is benzene six?

SPEAKER_05 0:44

Um six.

SPEAKER_11 0:46

See? See how look at look at us, right? Like how far are we from our basic science, right?

SPEAKER_04 0:50

Yeah.

SPEAKER_11 0:50

So it's it's it's so it's so it's just it's just like flat benzene rings. This is Rebecca. How do you say that's in Pinels? Pinals.

SPEAKER_05 1:02

Like finals with a P. Okay. Or the pie symbol. Is that that's what I draw for my students so they don't freak out when they see the bird fine.

SPEAKER_11 1:09

Nice. Yeah, right. Pinals for the pie. Yes. Very nice. Yeah, I say it's like the nerdiest possible way to get you.

SPEAKER_05 1:15

That's the one.

SPEAKER_11 1:16

I feel like you could draw like a pie. Oh, yeah, an apple pie.

SPEAKER_05 1:20

Three, you know, strokes for my symbol. That's right, it's a full, fully drawn pie.

SPEAKER_11 1:25

Yeah, that's nice. Um, assistant professor of chemical engineering. That's right. Stanford University. Okay.

SPEAKER_07 1:34

That's all I got for that's all I got.

SPEAKER_05 1:37

That's okay. So right now we're sitting in the Chem H Institute. So I'm also a part of this really cool institute uh that is meant to be interdisciplinary, uh, combining chemistry, uh, engineering, medicine for big problems in human health. Yeah, yeah. That's where the chem H name comes from.

SPEAKER_11 1:53

How'd you end up, how'd you end up here? Like what was your postdoc?

SPEAKER_05 1:56

Yes, my postdoc was in neurosciences uh over at MIT at the Pacauer Institute. But before that, I was in chemical engineering. So I was already kind of interdisciplinary uh based on my training, and then this was a really good home to you know pursue both the nano side of my research and trust as well as the neuroside. So uh and for you know, the big problem in human health that we're trying to tackle is Alzheimer's disease and neurodegeneration, more probably. So it was a really lucky find that um not only would chemical engineering um the Department of Chemical Engineering be a good fit, but also the Chemich Institute.

SPEAKER_11 2:32

Yeah, that's cool. Yeah. Um was it always Alzheimer's for you? Is that what it always sort of like led the charge from back into like undergrad and stuff?

SPEAKER_05 2:41

You know, no, it wasn't. I um I was a very conventional chemical engineer through undergrad. What is I'm so curious what a chemical, what a conventional chemical engine is a chemical engineer does things like study the kinetics of a reaction. Okay. Uh and trying to b develop better catalysts to make uh more of a reaction product or limit a byproduct, things like that. So conventional chemical engineering, I typically think of three areas uh thermodynamics, kinetics, and transport phenomena. So my underground research was like literally building reactors for biomass conversion with heterogeneous catalysis.

SPEAKER_11 3:18

So very biomass conversion with heterogeneous catalysis.

SPEAKER_05 3:23

Yes, so heterogeneous meaning uh different uh phases. So um we were doing uh Converting what to what?

SPEAKER_11 3:31

Um biomass conversion is that like carb carbon dioxide sequestration, or like what is not quite what were we doing?

SPEAKER_05 3:37

We were uh converting different uh uh oils uh into usable products.

SPEAKER_09 3:43

Like petroleum.

SPEAKER_05 3:44

Yeah.

SPEAKER_09 3:44

Yeah, yeah.

SPEAKER_05 3:45

It's been so long. Uh we're doing uh decarboxylation reactions with the test feed stock like palmetic acid.

SPEAKER_10 3:55

Just like don't want that carboxyl group.

SPEAKER_05 3:57

Yeah.

SPEAKER_10 3:58

Like don't want that. Yeah.

SPEAKER_05 4:00

But I I quickly realized that was not uh my particular passion.

SPEAKER_10 4:04

No.

SPEAKER_05 4:05

Uh no, and it was really interesting. I just um I got really more excited, even more excited, when I did a summer research program uh actually at the Colorado School of Mines, uh doing nanoparticle synthesis. Okay. So it was in an organic chemistry lab, totally different to me, although it sounds similar, chemistry versus chemical engineering. It's very different. Um, but we were doing silicon-based quantum dots, and I just got really fascinated by nanoparticles. So that is where my my love of nanoscience uh first nanoparticles just being like the size. Super small.

SPEAKER_11 4:41

But literally just like nanometer.

SPEAKER_05 4:42

Yes.

SPEAKER_11 4:42

That's what did like as opposed to like milliparticles or like yeah, microparticles. Yeah, microparticles. It's just nanometers.

SPEAKER_05 4:48

Yeah, so we typically define nanoparticles anywhere from one nanometer up to um even hundreds of nanometers. People still call those within the nanoparticles. Yeah. Um but then it becomes microparticles. And it becomes microparticles once it's a thousand nanometers. Um but uh yeah, from there I actually did my my PhD work more on the nano side, or very much uh on the nano side. So uh developing uh nanoparticle technologies to probe and um modify biological systems, um, but more much more fundamentally looking at how nanoparticles interact with biomolecules. So very fundamental thinking about.

SPEAKER_11 5:28

I'm really curious about the size. Yeah. Um so just trying to like sort of put it in in like a so there are carbon dioxide molecules, right? Um what's their like that's like angstroms? Like, yeah, yeah, yeah. How how many powers of 10 smaller than a nanometer is that?

SPEAKER_05 5:50

Uh angstroms?

SPEAKER_11 5:51

Yeah, should I should know that. I should I that's embarrassing. I should know.

SPEAKER_05 5:53

No, that's okay. It's a weird, I almost never use angstrom.

SPEAKER_11 5:56

Yeah.

SPEAKER_05 5:56

Um but yeah, nanometers being 10 to the minus nine. So um uh nanometer particle can have, you know, sorry.

SPEAKER_11 6:03

What are angstroms?

SPEAKER_05 6:04

What are they?

SPEAKER_11 6:04

Like 10 to the minus what?

SPEAKER_05 6:05

Oh, 10 to the minus nine.

SPEAKER_11 6:06

Oh, is an angstrom? Sorry. Is a nan is a nanometer.

SPEAKER_05 6:09

Oh, it's like right there.

SPEAKER_03 6:10

It's right there. Oh yeah.

SPEAKER_11 6:12

Okay. Yeah, so that's that's kind of what I was going for. So um so all you would need then, so a carbon dioxide molecule is measured in in angstroms, right? But it's probably like five angstroms or something like that.

unknown 6:23

Yeah.

SPEAKER_11 6:23

I mean, I don't know I'm somewhere around there. I'm I'm totally that's like a wild.

SPEAKER_05 6:27

So for context, the carbon nanotubes that I worked with, their diameters are on the order of one nanometer, but their length is hundreds of nanometers. So they're really, really high aspect ratio, but they're still nanopark.

SPEAKER_11 6:40

Well, that's how we're gonna build the space elevator.

SPEAKER_05 6:42

Oh, apparently.

SPEAKER_11 6:43

Carbon nanotubes, right? Like that's the whole plan. I don't think so. I think we I think we gave up on that. Yeah, only in only in sci-fi.

SPEAKER_05 6:49

We have found out that carbon nanotubes are useful for many other things.

SPEAKER_11 6:52

Turns out the world is spinning. Yes. And like when you spin that fast, uh it there's a lot of elevated air friction. Yeah, it's uh yeah, there's a lot of uh there's a lot of friction there. Yeah, a lot of angular angular momentum to manage. Yeah, yeah.

SPEAKER_05 7:04

Yeah, thank you.

SPEAKER_11 7:05

That's so funny. Yeah. Uh what you were saying?

SPEAKER_05 7:07

Oh, um, just for carbon nanotubes, uh, a very good use case for them is the fact that they're fluorescent. Uh and not only are they fluorescent, but they're fluorescent in the near-infrared region.

SPEAKER_08 7:17

So This is okay, this is super cool. Wait, okay.

SPEAKER_05 7:20

So did you have a shine light on them? Yeah, yeah. Uh and then they so you excite them with one wavelength and then they emit in another. But um and we do that all the time.

SPEAKER_11 7:29

I gotta ask you, I'm sorry, I gotta ask you a question. What's the um what's the how many carbon molecules is the circumference of the tube?

SPEAKER_00 7:38

I'd have to draw it out. It's gonna wild.

SPEAKER_11 7:40

Oh, we gotta let's do it. We got it. We got a whiteboard right here. Um But it's but like is it like six, twelve, twenty?

SPEAKER_05 7:47

In terms of um so it's a graphitic lattice, so they're benzene rings.

SPEAKER_11 7:51

Okay. Um benzene is just five, right? Or is benzene six?

SPEAKER_04 7:55

Um six.

SPEAKER_11 7:57

See? See how look at look at us, right? Like how far are we from our basic science, right? Yeah. So it's it's it's so it's so it's just it's just like flat benzene rings.

SPEAKER_05 8:04

Like, no, so that's um okay. So the thought experiment for how you make a carbon nanotube, but it's not actually how they're made, is if you take a monolayer of graphene, single layer, and you kind of roll it up.

SPEAKER_01 8:15

Yeah.

SPEAKER_05 8:16

Um, that's not how they're made. But um, as a thought experiment. So it's a single layer of a graphene sheet in a cylindrical geometry. You can imagine you can also have multi-walled carbon nanotubes, so multiple layers of those graphene sheets.

SPEAKER_11 8:29

But you don't need to wrap it, but if you've got benzene rings, there are already rings.

SPEAKER_05 8:33

Uh um, it's a benzene ring um repeated many, many times. And then that whole surface is the graphene. So you're rolling it up.

SPEAKER_11 8:43

Oh, interesting. Oh, okay. So the so the benzene ring itself isn't the pathway through which the Oh, yeah, I see. Yeah, yeah.

SPEAKER_05 8:49

So it's a series of many, many benzene rings together. Okay. And what's useful about that is that the benzene rings, they have these double bonds. Um, so you have electrons um uh that allow it to be uh personally.

SPEAKER_11 9:04

Aromaticity is what's gonna do it is what's gonna do it. Exactly. Yeah, yeah. Yeah and then and then all kinds of stuff with the um so what kind of so what what's the um emission spectrum?

SPEAKER_05 9:17

Yeah, so uh depending on the diameter of your carbon nanotubes, you have a different uh emission spectrum. Yeah. Uh this is actually a project I'm just finishing up now, even for my PhD work, it's a continuation of that.

SPEAKER_07 9:31

It's always fun, finishing up the work from before. Yes while you do, yeah.

SPEAKER_05 9:34

It is fun. Yeah, it never ends. Your projects never end.

SPEAKER_11 9:37

Um but not if they were good projects that have purpose, purpose, and weight.

SPEAKER_05 9:42

They end up with more questions. That's right, that's right. Good science.

SPEAKER_11 9:45

Yeah, good science.

SPEAKER_07 9:46

We we we create more questions than we answer. That's right. Very good.

SPEAKER_05 9:49

Uh so what we in that case, um, I guess in my initial PhD work, you usually work with these as a mixture of different diameters, um, ranging from like one nanometer to maybe like 1.5 nanometers. So it's a pretty small range, but it's a mixture. But if you separate them out based on diameter, that's gotta be like five benzing rings.

SPEAKER_11 10:11

Right?

SPEAKER_05 10:12

It's more than that.

SPEAKER_11 10:13

Is it?

SPEAKER_05 10:13

Yeah.

SPEAKER_11 10:14

Because if it's a nanometer, that's only 10 angstroms.

SPEAKER_05 10:17

Um a nanometer diameter.

SPEAKER_11 10:20

Right, it's only 10 angstroms. So I mean, if you can measure now, I'm so curious.

SPEAKER_05 10:27

We can do that after. Um, but point being, yeah, yeah, yeah, yeah. Depending on what the diameter is, um, you get a different uh emission spectrum, but it's all in the near Fred region.

SPEAKER_11 10:38

You actually design it? I'm sorry.

SPEAKER_05 10:40

We don't make the nanotubes.

SPEAKER_11 10:42

Well, because what I'm thinking is like it's like it's like music. Like, could you create a diameter? Is like is the emission that you achieve based on the the the wavelength um mapping somehow the wavelength of the emission, mapping somehow to the diameter of the tube? Um yeah, is that actually like directly yeah, yeah.

SPEAKER_05 11:02

So people think of this like band gap engineering. So depending on what your nanoparticle is, in this case, the that chirality of the nanotube, you get a different um excitation emission kind of factor.

SPEAKER_08 11:14

Yeah, yeah.

SPEAKER_05 11:14

Yeah, you could imagine if you have, so I think we zoomed in really um deeply, but to zoom out, the whole point of this is we want to use these nanotubes for imaging and sensing. And so you can imagine if you have one nanotube with certain fluorescent properties that's sensitive to one analyte and another nanotube with different fluorescent properties that is sensitive to another analyte, you could do multi-plex sensing. So that's one of the dreams in the field.

SPEAKER_11 11:39

Where you're gonna tie these to things that then like land in specific places in the body, and then you're gonna, and then that's what you're that's how you're gonna use it for imaging.

SPEAKER_05 11:46

Uh in this case, we often we design the sensor for a particular analyte. I mean, the best uh version of this has been for the doprine sensor. Um, so you have a carbon nanotube, you functionalize it, you put some polymer or something on the surface, um, and that gives the nanotube water stability, but also specificity to some molecular binding event.

SPEAKER_03 12:09

Yeah.

SPEAKER_05 12:09

And you have to screen through many different coatings to find, you know, what is specifically going to cause that analyte to uh interact with that polymer on the nanotube in a way that elicits a change in the fluorescence. So that's what I spent a lot of my PhD thinking through.

SPEAKER_11 12:27

So you want it to bind and in the process of binding, somehow create some sort of conformational change in the tube so that you get some change in the nanotube. Oh, yeah, that's still it's it's way more difficult than like we just need to get it there.

SPEAKER_03 12:41

Yes.

SPEAKER_11 12:41

Yeah.

SPEAKER_05 12:42

So first it's a lot of sensitivity.

SPEAKER_11 12:43

It actually shifts the shape of the tube.

SPEAKER_05 12:45

It shifts the uh shape of the polymer so the nanotube doesn't change. It's um kind of a static um system itself, but when the polymer changes on its surface, um, the nanotube fluorescence is very sensitive to that local change. So then you get a change in that fluorescent.

SPEAKER_10 13:04

Yeah, and it's all near infrared.

SPEAKER_05 13:06

Yes, so you can see through things, which is really valuable.

SPEAKER_10 13:09

Yeah. Um but only very not very far.

SPEAKER_05 13:12

No, well, yeah. It depends. I think there's been a lot more work on that area doing things like um two photon uh microscopy. But my my focus was really on, you know, how the nanoparticles interact with biomolecules. Um like very fundamental like protein-nanoparticle interactions, and then can you use that as a design tool for new nanosensors? So it's an example, yes.

SPEAKER_09 13:37

How do proteins and nanoparticles interact? Yes, like and nanotubes interact. So we often don't see this is so cool. Yeah. Oh my god.

SPEAKER_05 13:44

What happens is the nanotubes, you know, you make these beautiful sensors, they work really well in a clean system in the lab.

SPEAKER_11 13:50

Yeah, yeah.

SPEAKER_05 13:51

But then you go put them in.

SPEAKER_11 13:52

This is a story of what I do as a psychiatrist. Yeah. Yeah. Everything's great when it's clean. Yeah.

SPEAKER_05 13:57

And then you put it in.

SPEAKER_11 13:58

You get like real people and it's like totally useless. Yeah.

SPEAKER_05 14:01

Messy, complex biological system, and you get very unpredictable results.

SPEAKER_11 14:06

Yeah.

SPEAKER_05 14:06

Um, so I was thinking a lot about what happens in that step when you have what's called protein corona formation. So proteins attack but corona as in light?

SPEAKER_11 14:15

Uh the light corona.

SPEAKER_05 14:17

No, so that's but that's what it was named after um kind of the corona, the eclipse. Um it looks like. So you can imagine in that case, I guess um the sun or or uh yeah, the sun would be like the nanoparticle, and then the corona, those kind of tendrils of light are what the proteins would look like decorating the surface of the nanoparticle. Okay. Yeah. So that's the idea. Um uh, or or that's rather what happens. But then we wanted to know, you know, what drives that process, what governs those interactions, um, and use what we learn, kind of those fundamental So what what governs those interactions? So interesting.

SPEAKER_07 14:55

It's fantastically interesting.

SPEAKER_05 14:56

So, yeah, so many things govern those interactions. It's really hard to completely avoid it, but you can often use different strategies to mitigate uh adsorption, or you can try to adsorb the right kinds of proteins. So um I think uh there's a yeah, there's a lot of work being done in this field, and they haven't reached a strong conclusion of if I start with nanoparticle X and put it into system Y, get result Z. Yeah, that's where we want to be, yeah, uh to have generalizable rules, but we're not quite there. So some of my work was looking at these carbon nanotube sensors compared to more conventional nanoparticles like polystyrene. Um plastic.

SPEAKER_11 15:40

Yeah, I just like yeah, I always think of styrofoam for some reason. Is that what poly is polystyrene the the um it's I would, you know, I don't know.

SPEAKER_05 15:48

Um I'm not a I'm not a plastics person, but yeah, we can um styrofoam is very, very plat.

SPEAKER_11 15:53

It's like the most polymer. It's like it's like pure oil product. Yeah, yeah, yeah.

SPEAKER_05 15:58

Um but uh sorry. No, that's okay. That's my training out there.

SPEAKER_07 16:05

There's we're not going, we're not actually going anywhere in particular. That's the thing.

SPEAKER_05 16:09

That's okay.

SPEAKER_07 16:09

Unless there's somewhere you want to go.

SPEAKER_05 16:11

I mean, so I guess I realized I'm not really answering your your question, and we'll get to the Alzheimer's aspect. Oh, I know what I wanted to say. Yeah, yeah. Yeah. You know, what you asked, like what are the driving forces? Um and I think what's really interesting is now taking the framework where we looked at, you know, what drives these interactions, um, you know, enthalpic, entropic kind of contributions, but we we also looked at more recently, we looked at lipid nanoparticles. Um so those are really important because those carrying are those carry um the mRNA-based vaccines, like COVID vaccines.

SPEAKER_01 16:44

Oh, interesting.

SPEAKER_05 16:45

Yeah. So um that's been a very uh timely sort of pursuit that it's it's important to study these lipid nanoparticles with the protein corona problem. Um, I would say for the most part. We think so. Then it's how does the lipid nanoparticle interact with the vaccine with the with whatever the uh in so I guess I should back up for lipid nanoparticles, we're really good at oh beauty. We're really good like lipid nanoparticles with local delivery, but we haven't quite figured out more systemic delivery. So you can't just or in most cases, you can't get lipid nanoparticles injected into the blood and have it go where you want it to. You have to get it injected into your ARN, right? To uh for more local delivery. So the goal is that we can move towards systemic delivery and have a nanoparticle formulation go to a certain part of your body. Yeah. That often things go to your liver and we want to sometimes to hold the liver. Yeah.

SPEAKER_11 17:46

Is it because once it's in the body, proteins find it and attach to it?

SPEAKER_05 17:49

Yep. And those proteins direct it down to the liver.

SPEAKER_11 17:52

Of course, which is like that's how the body functions is to use is to do that to get things where it needs to be.

SPEAKER_05 17:57

Yeah.

SPEAKER_11 17:58

Yeah. And anything that comes in from the outside, it's gonna rapidly like let's yes, yeah, let's label this and get it where it's gotta go. Yeah.

SPEAKER_05 18:05

So how could we, you know, hijack some of the routing uh processes that are already employed by the body to go elsewhere?

SPEAKER_01 18:13

Oh, wow. So interesting.

SPEAKER_05 18:15

Yeah. So now let me answer your question about, you know, why Alzheimer's. So um I spent a long time thinking about a lot of fundamental things. Um, and then COVID hit. And then, you know, we're stuck at home. We're trying to think how can we benefit uh humanity and society. So um I developed this idea to make a nanosensor for COVID using all the principles we'd learned uh from protein nanopartal interactions. And, you know, it worked pretty well. It was kind of an uh exciting proof of concept, but that made me realize I wanted to go a bit more applied uh for my future work in a way that could maybe more directly benefit people.

SPEAKER_12 18:53

Yeah.

SPEAKER_05 18:53

Um, and at the same time, unfortunately, my grandmother was rapidly declining and uh I mean before even before COVID um and she had passed away. Um, and it was due to some dementia. Technically, with Alzheimer's, you know, you need to do an autopsy and you know, yeah, dementia's uh yeah, but dementia is a multi-pronged thing. Yes.

SPEAKER_11 19:15

And sometimes sometimes we can find out what it really is, but a lot of times it's just Dementia. Yeah, and a lot of times we call it vascular because it's yeah. Yeah.

SPEAKER_05 19:23

So that was uh very uh transformative for me to try to think of, you know, what how could I use what I have done in a way that would allow us to understand this disease that was so frustrating that we didn't know, or we still don't really know, you know, what are all of the mechanisms that together drive this very Yeah, we know the after the fact, but we don't know what yeah, we can like now that it's happened, we can look and say, yeah, tau tau particles and things like that, right?

SPEAKER_11 19:50

Yeah.

SPEAKER_05 19:51

So that's why I chose to study Alzheimer's disease.

SPEAKER_11 19:55

What uh neurofibulary tangles. I don't think that's is that Alzheimer's? Yep. The neurofibulary, these are this is like med school coming, where it's like there were all these like specific markers, and they would and you'd get tested on like this marker means this and this marker means this, but it was like you're never right.

SPEAKER_05 20:10

And so, and yeah, so I guess with that classification, we often think Alzheimer's disease amyloid tau. Yeah. But if you look back at the original disease description, and it's not it is now, but it it has not historically been as talked about and pursued, there were also lipid um uh accumulation. There was lipid accumulation in the Alzheimer's brain, and there is repeatedly this kind of hallmark. Um, it's really hard to study lipids. So we've um so for proteins, uh, we have a better way to probe them with antibodies. Um, and we can sensitively probe those proteins and we can connect from a protein to the gene level.

SPEAKER_11 20:51

And we've got so much now engineering capacity at the gene level that we can do all kinds, we can like make this tag that's you know, like build a gene that's gonna make this very specific tag that will attach to this protein, right?

SPEAKER_05 21:01

Right. But for lipids, lipids just fat fumbles. Looks they look very similar to each other. It's hard to distinguish um lipid A from lipid B the way that we can distinguish proteins, as well as they're not directly tied to a gene. So it they've just been harder to study. Um and they aren't tied to genes?

SPEAKER_11 21:20

Or it's not we don't manufacture them in the same way.

SPEAKER_05 21:22

We don't manufacture exactly.

SPEAKER_11 21:24

Right, because we can't because we need to ingest long-chain fatty acids to make lipids, right? Yes, you can't we can't create diet.

SPEAKER_05 21:29

Yeah, some of them they come from proteins that you know are uh in uh involved in these kind of metabolic pathways. Yeah, yeah. Not like a direct connect connection. So I think just and and historically, I mean, there's been a huge amount of work on the amyloid and tau side. Yeah. Um, and sometimes, you know, the the timeline of when we discover things uh can kind of bias us into one uh bucket of what causes a disease.

SPEAKER_11 21:56

So we we engineer based on what we know.

SPEAKER_05 21:58

Yeah.

SPEAKER_11 21:58

You know, so there's all this work. You know, around the turn of the night, it's like it's all organic chemistry. That's when we discover vitamin D, and it's when we discover like all these things because we have discovered how to do organic chemistry. And so now that's what we're doing.

SPEAKER_04 22:11

Yeah.

SPEAKER_11 22:11

And then it becomes that's the uh That's the path we go down. And and all the explanations are too generalized, right? And then until you dis until we discover something, like a different yeah, yeah.

SPEAKER_05 22:21

Yeah. Yeah. Yeah. No, it's it's it is not unique to Alzheimer's um by any means. But um, how does the body direct lipids? Aaron Powell Well, I think uh that's something I'm really interested in is um Because the body must do it. Yeah. So the brain, we often don't think about this, but the brain is the single most uh cholesterol-rich organism. Oh, yeah.

SPEAKER_11 22:42

Yeah, oh yeah, yeah, yeah. And so that's a that's like why the statins can can lead to can lead to um confusion.

SPEAKER_04 22:48

Yeah.

SPEAKER_11 22:48

Yeah. So it's all well and good to like pull out all your LDL, but now but but now your brain doesn't work. Yeah. Yeah, yeah.

SPEAKER_05 22:54

So there's a lot of um, you know, local production and use, but then there's also local waste in the brain. And sometimes the brain is not as um well suited to store that waste. So it gets, you know, uh uh, you know, removed to the periphery, but sometimes it does remain in these cells and you get accumulation of lipids. So um that's something I'm really interested in. Uh the connection there, APOC.

SPEAKER_11 23:20

So bubbles in the brain.

SPEAKER_05 23:21

Or lipid.

SPEAKER_11 23:22

Yeah, fat, fat bubbles in the brain. Yeah, yeah.

SPEAKER_05 23:25

Um ApoE, sorry. Yeah, no, uh, this this gene, APOE, is the single greatest um genetic and and common genetic risk factor for sporadic Alzheimer's disease.

SPEAKER_11 23:36

Yeah, because if you have two of them, it's like it's not not a not a win. Yeah, yeah.

SPEAKER_05 23:41

Yeah, yeah. So ApoE4 is the risk form, ApoE3 is the more common form, but there's even protective forms like ApoE2 that are protective against um Alzheimer's, but they're actually they raise your risk for other things in the periphery. So uh this ApoE gene encodes the protein, apolipoprotein E. Yeah. And that sits on these lipoprotein particles, different than lipid nanoparticles, which we talked about before, but these lipoprotein.

SPEAKER_11 24:07

It's a mixture of lipid and protein.

SPEAKER_05 24:09

Uh, yes, exactly. Yeah, yeah. And these are transporting lipids from, you know, where those lipids are um produced to where they need to be used, oftentimes from cells called astrocytes to neurons. Um astrocytes make lipids? Yeah.

SPEAKER_11 24:23

Stop it. Really?

SPEAKER_05 24:25

They do a lot of things.

SPEAKER_11 24:26

When did we figure that out? Is that relatively recent that we figured that out? Because I thought up until very recently we weren't sure what astrocytes did, and we also thought maybe they were the brain's macrocytes.

SPEAKER_05 24:34

Yeah, I guess I'm not sure the exact date, but I think there's been a lot of work recently on glia, uh, these kind of support cells. Yeah. We just we assumed everything in the brain with neurons.

SPEAKER_11 24:47

Yeah, we do this thing where it's like all that other stuff, it just has no purpose. Let's just take those spleens out. We don't need those. That doesn't do anything. Right.

SPEAKER_05 24:53

Oh wait.

SPEAKER_11 24:54

Yeah, it turns out immunology. Yeah, yeah.

SPEAKER_05 24:57

So um these astrocytes are making ApoE and they're making lipids and they're they're moving those lipids over to neurons. And ApoE4, the risk gene, is that at that transfer process, we think, um, as well as it has, you know, other issues like it self-aggregates and things like that. So um in my lab, what we're trying to do, uh, and as well as this was work that I started on my postdoc, was trying to study this at the pro the particle level. Um, what happens if we just make the particles synthetically to drive this process uh into a better outcome than if you had the A4 particles that are not really doing their job as well?

SPEAKER_11 25:39

Make which particle? The apolipoprotein particle? Yes. You know, so how so what's the difference between E3, E E2, E3, and E4? Is it the actual apolipoprotein that is created is different?

SPEAKER_05 25:49

Yes, the protein is different.

SPEAKER_11 25:51

Um So the lipid part is the same.

SPEAKER_05 25:54

Well, we don't know. So that's something we're trying to discover. Or the lipids that are part of the particles. We know what the protein looks like, but we don't yet fully understand how that relates to the particle uh kind of biological chemical.

SPEAKER_11 26:10

Because all the machinery we have to interrogate that can only make proteins. Yeah. It it can't make the lipid component stop.

SPEAKER_05 26:19

So I think it's uh So how do you make the lipid component?

SPEAKER_11 26:21

I mean, that's just fatty chain, that's just fatty acid metabolism.

SPEAKER_05 26:24

We put the the lipids together. Um, you know, we have this kind of nanoparticle synthesis route that we can do in the lab um to make these particles. Uh I'm excited to publish on this in the future, which which I will share, you know, more details on. But for now, yeah.

SPEAKER_07 26:40

You can keep it all hidden. So yes, you can hide it from our very large audience. That's great, yes. Yes.

SPEAKER_05 26:46

But you can mix like lipids and and proteins together in a way that maybe mimics what you see in the brain, in the cerebrospinal fluid of the brain or the interstitial fluid. And you can then, you know, characterize them. And like you said, everything's clean in a test tube or in in those uh clean contacts, but you can learn a lot about how they function. Uh, and then you can also see how they clump.

SPEAKER_11 27:09

Do they not clump? Do they bump into the right do they stick to things? Yeah, yeah, yeah.

SPEAKER_05 27:13

Yeah, yeah. So um that's one uh you know part of my lab that we're kind of expanding on the nanoparticle theme in a way that's you know much more closely tied to like bio-inspired, if not biologically isolated nanoparticles.

SPEAKER_11 27:31

If you could figure out a way to have a just a factory system, just like just have uh an in lab factory that can that can take the gene for apalipoprotein X, right? And then just make it from the gene.

SPEAKER_05 27:51

Yes. And so you can imagine this is we often think about lipid nanoparticles or lipid-based nanoparticles as a carrier for a therapeutic. But in this case, what I'm saying is the the lipid-based nanoparticle is itself a therapeutic.

SPEAKER_11 28:07

Yeah, yeah, because it's because it's maybe the cause of like we know we know that it's the that's the risk gene. Yeah. So clearly it's relevant, you know. So it may not be that the product of the gene is, but like sounds reasonable.

SPEAKER_05 28:19

Yeah. So yeah, that's an exciting or that's a research direction that I'm uh really excited about. And we'll see what we can learn over the next few years. But I think we're at a point right now where we have like really good data from you know the genetic side that informs us about the importance of lipids. And I'm not working on this in a vacuum, of course. You know, there are many people in this direction in the same building.

SPEAKER_11 28:45

Yeah, to discover that there's just this empty space. Yeah. Um, where there's clearly this thing that's important, and we just don't know how to if we can't make it, then it's really hard to study it.

SPEAKER_05 28:55

Yeah.

SPEAKER_11 28:56

Yeah. Oh wow.

SPEAKER_05 28:58

So that's a long answer.

SPEAKER_11 29:00

Which has nothing to do with the blood-brain barrier that so it's well, it could, it it might. Well, right, right. Because you said it transfers to the periphery, and I immediately thought, right, yeah, yeah. So on the other side of my I'm curious what you think of the whole Einstein's brain had a lot of astrocytes thing.

SPEAKER_05 29:15

Oh, I I don't know. I I have heard of this, but I don't know. Um, I haven't looked into the primary literature about yeah, I'm not sure there's a lot of primary literature on it.

SPEAKER_11 29:26

Like, I mean, as far as I know, his brain was like like not even studied. It was like captured somewhere like in a jar somewhere.

SPEAKER_05 29:32

There's some crazy story about um the the neuropathologist who kind of stole the brain, right? Um I don't know the full details, but I I think it they only recovered Einstein's brain fairly recently.

SPEAKER_11 29:47

You're like not, it was well, I'm not sure. I I don't know, I don't really know the story. Yeah. Then there, I'm sure there's plenty of like that real stuff, like, yeah, we could Wikipedia that and figure out what reaction is.

SPEAKER_05 29:56

Yeah, um but on the blood grain barrier side, yeah. Kind of in in parallel to the work I did in my postdoc on the lipid side, I was really interested.

SPEAKER_11 30:06

That wasn't enough.

SPEAKER_05 30:07

That wasn't enough.

SPEAKER_11 30:08

Okay, you decided, okay, yeah. This is how you become a Stanford professor.

SPEAKER_05 30:11

You you get distracted by many problems.

SPEAKER_11 30:15

Yes, and and spend your time solving them. Yes, hopefully. Yeah.

SPEAKER_05 30:18

Um so on the blood brain barrier side, um, there's been a lot of work showing that indeed the human brain and blood brain barrier is different than model organisms. Um and so we need models.

SPEAKER_11 30:31

Um like like it's just different than in mice. Yes. Like the human BBB is just different than the mouse one. Yeah. In what ways?

SPEAKER_05 30:38

It's leakier. Um and the cell type um, you know, components and and the uh characteristics of those cells is slightly different, such that when a drug works to get delivery in a mouse, yeah, it might not work in a human. And we know that to be the case.

SPEAKER_11 30:53

How is it possible that I mean, I guess, I mean, maybe just like very late, like is it the same as in primates?

SPEAKER_05 31:00

It's closer to primates.

SPEAKER_11 31:02

But even different from primates.

SPEAKER_05 31:03

Yeah.

SPEAKER_11 31:03

Wow.

SPEAKER_05 31:04

Yeah. Wow.

SPEAKER_11 31:04

So there's evolution even at the very tail end there. Yeah. So, and that's something that it's such a complex system that if you were to make changes, like it the system wouldn't function. Yeah. So it would have to be relatively conserved.

SPEAKER_05 31:17

It's a conserved idea, even down to you know, Drosophila. I was actually talking to someone.

SPEAKER_11 31:22

Really?

SPEAKER_08 31:23

About fruit flies have a blood brain, but do they even have a brain?

SPEAKER_05 31:26

They do, but it's it's a different, you know, different cells.

SPEAKER_08 31:29

Which calls into question the the ethics of being so brutal to the fruit flies.

SPEAKER_05 31:34

Yeah, I'm not going to raise that here.

SPEAKER_08 31:37

Those poor fruit flies.

SPEAKER_05 31:38

I I'm brutal to the human cell uh models I build.

SPEAKER_01 31:41

Outside of the body?

SPEAKER_05 31:42

Yeah. In vitro models.

SPEAKER_01 31:44

Yeah, yeah. Yeah.

SPEAKER_05 31:45

But um so this idea of okay, could we make a model that we could interrogate uh instead of trying to study um model organisms that don't really, you know, uh recapitulate what we saw.

SPEAKER_11 31:56

So if there isn't, that sounds like there isn't one. Yeah. Yeah. Um we can't and you can't do it in people, obviously. Like that's there are people who have tried. Uh don't look on them kindly.

SPEAKER_05 32:08

Someday money.

SPEAKER_11 32:08

Yeah, there's some history uh there. Yeah, that's me.

SPEAKER_05 32:11

No, but I think, you know, for for many different reasons, we want to develop a system that um we can learn about the human brain and vulnerable barrier. And the way that we can do that is using these human induced pluripotent stem cells. So IPSCs. Yeah. And the idea broadly there is that um you could take a skin biopsy.

SPEAKER_10 32:30

You have to tell me what IPCs are. Oh, okay.

SPEAKER_04 32:32

You have to I didn't know I if I could explain to the no, that's to the audience, whoever that may be.

SPEAKER_11 32:37

Like, no, but the whole the whole point of this is like all these podcasts that are like, you know, it's just like it's it's like I like I know what the like I know what these things are. Like, let's just talk about them. And it's not, yeah, I mean to you, I mean like I'm not frustrated with you, I'm like frustrated with podcasts, right? That's why the that's the point of this. Let's go.

SPEAKER_05 32:53

Yeah, yeah. Human IPSCs when we can make in theory whatever we want, but what we want to make are the cells of the human blood brain barrier.

SPEAKER_12 33:00

Yeah.

SPEAKER_05 33:01

Um, and then we don't just want to put them in um, you know, an easy geometry, like put them in two dimensions.

SPEAKER_11 33:08

Yeah, like just make a plane. Yeah, yeah.

SPEAKER_05 33:09

That's not representative of the human blood brain barrier is. So the human blood brain barrier is actually these capillary vessels.

SPEAKER_11 33:15

And so Yeah, I thought it was like really tightly woven.

SPEAKER_05 33:18

Yeah, these really um intricate kind of networks of capillary blood vessels. Yeah.

SPEAKER_11 33:23

And hence the blood brain barrier.

SPEAKER_05 33:25

Yeah. And so we want to guide self-assembly within a 3D kind of co-culture in a way that those vessels look like they do in a human brain. So we're able to do that. Um, and we want it to be in a format that we can look at to see, you know, how the disease might be evolving or how environmental perturbations might influence.

SPEAKER_11 33:45

Well, like once you once you have the functional replica, you can do anything. Yes. Yeah, yeah.

SPEAKER_05 33:49

It opens up many doors. So um that's an exciting direction of how close are you? Oh, I think so we have the preliminary model done um with the human blood-brain barrier on chip, so in a microphytic chip format. But there are certain tweaks that we want to make to make it even better um and more representative. Do tell.

SPEAKER_07 34:10

Yeah, do yeah.

SPEAKER_05 34:10

Well, that's a that's a what would make it better. Yeah.

SPEAKER_07 34:13

It's that, or is that this is where we're straying into information, information that should not be talked about until it's published.

SPEAKER_05 34:20

Not until it's yeah, almost there. Um to get the grants first. Yes, and student uh projects are just starting up, which is really exciting. Yeah. Um, and then we want this to be a testing bed for everything from really fundamental questions like how does mass transport work um in going from in the blood mass as in like large quantity or mass as in size of particle? Uh mass as in anything you would want to model, whether it's something that should be crossing the blood brain barrier or should not be crossing the blood brain barrier. So, how does it thinking about this from a chemical engineering perspective of like you have fluid mechanics in the vessel, yeah, fluid flow, but then you have some kind of interfacial mass transfer resistance at the blood brain barrier itself. But then after you get crossed the blood brain barrier, which, you know, that's a very challenging step, you then are in the brain. And the brain is not, you know, these kind of cells, um it doesn't have a lot of things sitting near each other. Yeah. It's a porous matrix, it's the extracellular matrix. So, you know, how does a, for instance, a nanoparticle navigate through that?

SPEAKER_08 35:24

Wait a second, wait a second, wait a second.

SPEAKER_11 35:26

How much of the brain is extracellular, like by percentage, is extracellular matrix and not actually cell?

SPEAKER_05 35:34

I'm not sure off the top of my head, but um you can imagine the pore sizes of that matrix are around like 50 nanometers. So it's pretty hard for, you know, we talk about wanting to get like these big um nanoparticles across the blood-brain barrier, but you know, even once you do that, what happens to the nanoparticles?

SPEAKER_11 35:57

Now you're in the goo, now you're in like a goo. Yeah, yeah. Like a, yeah.

SPEAKER_05 36:00

So, you know, trying to co-design a way to cross the blood brain barrier in a way that is also compatible with brain transport, I think is one of the big uh high-in-the-sky type goals.

SPEAKER_11 36:13

Yeah. I never really thought about how different as a tissue, as an organ, brain would be compared to other tissues, because most other tissues are largely cellular.

SPEAKER_03 36:21

Yeah.

SPEAKER_11 36:22

Right? Like the kidney is largely cellular, the functions are mostly cellular, right? And it's like densely packed cells. The liver, you know, the patocytes, densely packed cells, and it's right, it's cells doing stuff. Yeah. Muscle is just cells, right? Um, and there's maybe there is extracellular matrix, but it's not the majority of the space, at least not in my conceptualization of it.

SPEAKER_05 36:45

Yeah, no, and it it depends on the region of the brain too, right?

SPEAKER_11 36:48

So I assume high I assume higher would be more higher would be more matrix. Yeah. Like the further you go into cortex, the more frontal you go. It's probably more and more and more matrix, I would think.

SPEAKER_05 36:59

Yeah, I can't comment without first looking into it.

SPEAKER_11 37:02

Well, because if you think of, I mean, because if you think of things like the the um uh like the hypothalamus is so dense with cells, like so dense, um, very small and very dense with incredibly active um complex cells doing all kinds of things, right? And so much the brain is also, you know, axons. Um, but now I'm like, it would make sense for there to just sort of be like a mush that's like somehow a more active part of it than we think.

SPEAKER_05 37:31

Yeah. Just the consideration from a kind of an engineering standpoint of how to design uh with the system uh in mind.

SPEAKER_11 37:40

So yeah, that's where we're 50 nanometer po five 50 nanometer pores in in the extracellular matrix.

SPEAKER_05 37:46

Yeah.

SPEAKER_11 37:47

What does that even mean? Like Yeah, right, right.

SPEAKER_05 37:50

Yeah.

SPEAKER_11 37:51

Right, but a hole from where to where, right? Like a so like a pore between a cell and another cell. Because you're going from like one cytosol to another cytosol, or you're going from cytosol to extracellular, right? So like the pore makes sense to me. But if it's like there's just a bunch of extracellular matrix, which is like that pore isn't like it would have to be a tube.

SPEAKER_05 38:09

Uh yeah, like a pore, I guess you could conceptualize as a tortuous kind of tube uh uh with different kind of protein constituents holding it together. But I think uh, you know, there are where was I going to go with that?

SPEAKER_07 38:25

I don't know. This is this guy, this is she, this is where it gets cool for me. It's like I don't even know where we went anymore. I'm not even sure where we are.

SPEAKER_05 38:31

Yeah, for the blood brain barrier itself, I think you know, that's our focus for now. Um, but you can imagine making these models, these cellular models, in a way that you add more cell types.

SPEAKER_01 38:41

Yeah.

SPEAKER_05 38:41

Um, of course, neurons are important, microglia, like a dendrocytes. Yeah. Um and and you know, tuning the system in a way that you can model certain uh dysfunctional aspects of the how much do we actually know about how the blood brain barrier works? We have in humans.

SPEAKER_11 39:00

Yeah.

SPEAKER_05 39:01

I was going to say we've learned a lot from model organisms. Yeah. Um, as well as we I assume it's mostly mice. Mostly mice.

SPEAKER_11 39:08

Yeah, yeah.

SPEAKER_05 39:09

Um, and there's been a really nice body of work now where we are starting to build these human cellular models of the blood brain barrier, that we can look at it at a more molecular and cellular type level. Yeah. Um, but I I think there's a there's a famous quote by um George Box uh that you know, every model is wrong, some models are useful. And I think that's a really good way to think of it that you know, our models will never be perfect. And I'm the first to admit, you know, my blood brain barrier model is just not a human blood brain barrier, but it can allow us to learn certain things about how um, you know, certain chemicals or molecules might be able to pass, certain uh chemicals or molecules might not be able to pass, how we can engineer them to aid in passing, or how we could maybe strengthen up that barrier that becomes leakier with age or with disease.

SPEAKER_11 40:00

Okay, can I ask you about the blood brain barrier now? Like, because I you probably know this really well. Um how thick is it?

SPEAKER_05 40:10

So the the cells that make up the blood brain barrier are endothelial cells.

SPEAKER_13 40:15

Right.

SPEAKER_05 40:15

Uh those form the capillary, and those are surrounded by pericytes. And there's also this kind of basement membrane um coating.

SPEAKER_11 40:24

Like outside the parasites.

SPEAKER_05 40:26

Yeah, kind of around with the pericytes. And then those are surrounded by astrocyte end feet. So you can think of it as like three layers of cells.

SPEAKER_11 40:35

Um astrocytes are sort of like in the blood brain barrier and they just like shoot feet everywhere.

SPEAKER_05 40:39

They're feet are kind of stuck onto the vessel.

SPEAKER_11 40:42

Inside are they inside then, I assume? Outside.

SPEAKER_05 40:44

They're not the brain side.

SPEAKER_11 40:46

They're on the brain side. Yeah. So the That's what I thought of as inside.

SPEAKER_05 40:49

Oh, yeah. So that's that's a common thing that neuroscientists think brain out. Uh, and then uh, you know, other people in biology might think like body into brain.

SPEAKER_11 40:59

Well, because I think of it's the barrier to get into the brain. So once you're through the barrier, you're in the brain, right? Or you think of it the other way.

SPEAKER_05 41:06

I think of it like the blood is in your vessel, and that's kind of the the center, the core of your cylinder, and then you have things wrapping around that, and then the brain is outside of the cylinder.

SPEAKER_11 41:17

Okay. Okay, that makes sense. But if you're thinking of just an individual capillary, right? But isn't the blood-brain barrier like many capillary, like it's not, it's not just is it just a single layer of capillaries?

SPEAKER_05 41:29

It is a single capillary with those uh layers around it.

SPEAKER_11 41:33

And that's the full width of it. Um it's not like multiple multiple layers of this exact same thing.

SPEAKER_05 41:39

No, it's just a single, those layers of cells. But then you can imagine it's not just a single capillary in your brain, or else we'd all be in trouble, but it's this dense vascular network. Yeah. So the blood-brain barrier encapsulates like all of those capillaries together, where at each of those capillary surfaces you have that assembly of pericytes and astrocytes surrounding the well, and that's kind of what I'm asking is is is um so does the does the body manage to like, okay, so if this is the blood brain barrier, if my hand is a blood brain barrier, right?

SPEAKER_11 42:13

Is it is it the body is just it's all one one capillary width, and the body has just managed to squish a whole bunch of them together.

SPEAKER_05 42:20

They're distributed. Uh so uh you have a capillary bed, essentially, in 3D. So you have many different capillaries going off in all these different directions.

SPEAKER_11 42:32

That's my that's my is like so. That's my question, is the 3D component of it.

SPEAKER_05 42:36

Yes.

SPEAKER_11 42:36

Is like how many how how then how like if the blood brain barrier isn't just uh a web that's one dimension or one layer of capillaries, if it's multiple layers of capillaries.

SPEAKER_05 42:47

It's the it is uh all the capillaries within that vascular network.

SPEAKER_11 42:54

But single capillary. No, if I were to take a um like a punch, like a punch biopsy.

SPEAKER_05 43:02

Okay.

SPEAKER_11 43:02

Right? And I just do like a punch biopsy through the through like any point in the blood brain barrier, right? You'd see like little pieces of vessels in your And would it just be would I just see like the like it's just it's like whatever's, you know, like I get bone or whatever, and then I get brain, and then but then the blood brain barrier is just like whatever pieces of capillary I give, it's just it's just that one layer of like describing us well. Yeah, I'm yeah, I'm trying to, yeah.

SPEAKER_05 43:26

It is three-dimensional capillary network throughout the brain. I can wait, the blood brain barrier isn't it's not like a coating throughout the brain. No. And that's a common misconception. Yes. So if that works.

SPEAKER_11 43:40

But that's how it's taught in med school.

SPEAKER_05 43:42

Really? Yes.

SPEAKER_11 43:42

Oh because we learn about the blood the the the the the blood brain barrier windows, which are super important.

SPEAKER_03 43:49

Blood brain barrier windows.

SPEAKER_11 43:50

There I think there's four of them in the brain where where there are windows, um, where the blood brain barrier is thinner. And so like the hypothalamus is one of them. And it's it's a it's it's a way there there's there's different purposes for each one, but but one of them is um largely senses carbon dioxide.

SPEAKER_05 44:09

It it senses uh um uh the like a carboxylic uh carboxylic acid, I guess, the the the carbon dioxide the the acid form of um I think I know actually when you said windows, I think that's more of like a umbrella term of where the book it's not that the blood-brain barrier is suddenly leakier there. It's it's a different thing.

SPEAKER_11 44:33

Well, so this is because this is why this is my conception is not landing, right? Because it's clearly wrong. Um some models are wrong. Um so my conception is there is a brain and uh outside the brain is the blood, there is a barrier. And and which has always been weird to me because there's also all these blood vessels going into the brain, of course, right?

SPEAKER_05 44:56

So that's so let's follow that. So the blood vessels are going into the brain, say you have an arterial kind of diving into the brain, right? That will split off into this whole uh dense vascular, this capillary bed.

SPEAKER_01 45:08

Yeah, because I always wondered how do you actually how do you actually get nutrition and oxygenation to be free?

SPEAKER_05 45:13

So the it's estimated that no brain cell is further than um about 20 microns from a capillary.

SPEAKER_11 45:21

That's close. Yeah. Because what oxygen can go, like 100 microns outside. I think ox oxygen can go as I think as far as a hundred microns from a from the most from the nearest capillary.

SPEAKER_05 45:30

Maybe even a little bit less, but the the we need like really fast delivery of things like oxygen and nutrients.

SPEAKER_01 45:37

And a lot of delivery. Right.

SPEAKER_05 45:38

Yeah. That's why it's this distributed network. If you had a barrier around like the whole L. That's why it doesn't, then there's no way that you could get oxygen and everything into the the you know, um, interior.

SPEAKER_11 45:49

I feel like so then the then the barrier itself, it's not this, yeah, because then there's this like these the the the wind, the such like you know, they're called the um, it's it's Latin, I forget that it's vent something, like venton or something. Um but where you get, you know, it's how like the healthy thalamus can sense hormone levels um because it's got because it's the the blood brain barrier is thinner there. So like, you know, the large blood vessels coming up past that part of it, you know, can can sort of somehow be, you know, the the chemical composition can be sensed.

SPEAKER_05 46:17

Known as like circoventricular organs where there isn't really a blood brain barrier. And that's interesting that they they're calling it a window. Um I myself have never been to medical school, but um I typically think of, yeah, at the capillary level like super 3D, like very curved vessels.

SPEAKER_11 46:33

So that's why so it's not the capillary itself that's the blood brain barrier. The capillary is just the vessel. It's that, but it's the pericytes and the astrocytes.

SPEAKER_05 46:41

So those three components together make up what is known as the blood brain barrier.

SPEAKER_11 46:45

Are the capillaries actually meaningful, like outside the parisytes and the different capillaries than the rest of the body?

SPEAKER_05 46:50

Yeah. So they are held together by proteins. Each cell is held together by proteins that are um, they form things like these tight junctions. Yeah.

SPEAKER_11 46:58

And they're really there's a lot of things in the body that have tight junctions, though.

SPEAKER_05 47:01

They do, but these ones are very challenging to pass.

SPEAKER_11 47:03

You're even tighter junctions.

SPEAKER_05 47:05

As well as the cells themselves don't take up as much from the blood. So their rates of endothelial cells don't take up as much. They don't take up as much. So um the rates of things, you know, getting taken up by an endothelial cell and then kind of spit out on the prelo.

SPEAKER_11 47:22

Yeah. I had this image as you were describing it, and and and you talked about the like the fluid flow. And I was like, oh, it's kind of like when you walk into a store and they and they leave their doors open in the winter, and the way they actually the way they manage like keeping the heating in or keeping the AC in in the summer is there's like fan, like, right? Because just high velocity airflow is a very effective temperature barrier.

SPEAKER_13 47:44

Yeah.

SPEAKER_11 47:44

Um, that just the the velocity of flow alone isn't effective. Is it and so and so the barrier, it's not wow, what oh, this is so the barrier itself, it's not like there's stuff trying to get in and there's a barrier and we're gonna keep it. It's like the barrier is it's just it's really important.

SPEAKER_03 48:02

Blood.

SPEAKER_11 48:02

It's it's important for we just don't want stuff coming out of the blood. We just don't want stuff from the blood getting through that we don't want getting through. Right.

SPEAKER_05 48:09

So if you have some kind of infection, you do not want that getting into your brain. And the blood brain barrier is very selective for um certain toxins and pathogens to keep them on the blood side, as well as even just blood proteins.

SPEAKER_11 48:22

And how come the the brain can't the brain doesn't have a good way to um offload like swelling, doesn't have a good way to offload like when when blood leaks into the brain, right? It's like immediately toxic.

SPEAKER_05 48:37

Exactly.

SPEAKER_11 48:37

And then there's no good way to funnel it out.

SPEAKER_05 48:39

Yes. So when uh there's some kind of uh disruption of the blood-brain barrier, that's when things uh go downhill really fast, right? Um, but there's also these kind of slow- Yeah, like Alzheimer's.

SPEAKER_11 48:55

Just like Alzheimer's. Yeah. Yeah.

SPEAKER_05 48:56

So in that case, we think that it's uh, you know, vascular dysfunction leading to these kind of long-term slow issues.

SPEAKER_11 49:04

Wow. Where like maybe stuff's getting through that shouldn't, yeah, or isn't getting out that should. Yeah. I see why now, I see why now in is the brain side. Or no, I'm sorry, out is the brain side. Yeah, could non-cause what's the out out is the brain side because in is in the blood vessel. Yeah. Yeah, yeah.

SPEAKER_04 49:21

Yeah.

SPEAKER_11 49:22

And I and I my question no about like what's that was totally off base, like my my my model was just wrong.

SPEAKER_05 49:28

I'm glad I could uh because a lot of people, and this is how it was described to me as a non-medical student, but I thought of it sort of like a castle with a moat around it. Yeah, that's right. But it's more like you know, uh roots in soil, like it's very I was gonna say like individual people wearing like suits. Sure.

SPEAKER_07 49:48

Wearing like protective suits, like walking through the castle. We've all got our protective suits on. But uh yes, you're a spencer. That's sorry, yeah.

SPEAKER_04 49:56

Like the pencil analogy continuation.

SPEAKER_11 49:58

Yeah, yeah, yeah. Yeah. Cool. What time is it?

SPEAKER_05 50:02

Um, it is well, actually, I've been correct for daylight savings, but it is just past four. 412.

SPEAKER_11 50:07

Oh, nice.

SPEAKER_05 50:08

Um fix my wash.

SPEAKER_11 50:11

So when you're making a blood brain barrier on a chip, you're creating the endothelial layer and the parasite layer and the astrocyte feed.

SPEAKER_05 50:20

Yes. And what's really cool is that we don't put them together in that order. We put them in a hydrogel and they find each other and they form the vessels, which is crazy.

SPEAKER_11 50:31

It's adorable.

SPEAKER_05 50:33

They find each other. It's so adorable.

SPEAKER_11 50:36

So well, okay, but take me through that. Like, what is that what does that mean? It's just like what are the things you put in?

SPEAKER_05 50:42

If you put in the right numbers of cells and the correct ratio in a hydrogel that they can kind of remodel to find each other.

SPEAKER_11 50:49

How do they move through the hydrogel? Just diffusion?

SPEAKER_05 50:52

Um, cellular movement.

SPEAKER_11 50:54

So they we start out Endothelial cells have flagellum.

SPEAKER_05 50:58

No, no, no.

SPEAKER_11 50:59

And cilia? No. I'm so confused here now.

SPEAKER_05 51:01

No, no, no. They just they kind of they start out, you know.

SPEAKER_11 51:04

We Do you actually like chop off the astrocyte feet? Is it like astrocyte feet that have no astrocyte?

SPEAKER_05 51:09

No, we don't think fairing interview.

SPEAKER_11 51:11

That's horrible.

SPEAKER_05 51:12

So we did we do dissociate them. So we start out in 2D. We make the cells from IPSCs to say an endothelial cell, and we dissociate that. And that's kind of an enzymatic process. We lift them off the window.

SPEAKER_08 51:22

Wait, wait, wait, wait, okay.

SPEAKER_11 51:23

Okay. So wait, so you make you make an endothelial, you make the endothelial cell, and and you've and somebody you must have like many people must have characterized the because it's got many steps from from an induced pluripotent stem cell to like a blood-brain barrier endothelial cell. So that's all been characterized.

SPEAKER_06 51:37

Yes.

SPEAKER_11 51:38

And you can just be like drop these chemicals in, and it becomes exactly that endothelial cell.

SPEAKER_05 51:43

It's called a brain microvascular endothelial cell.

SPEAKER_11 51:46

There you go. Yeah. BMAC.

SPEAKER_05 51:47

We dislocate the BMAX. Yep.

SPEAKER_11 51:49

BMX.

SPEAKER_05 51:50

BMEC.

SPEAKER_11 51:50

BMEC.

SPEAKER_05 51:51

Yeah.

SPEAKER_11 51:52

Oh. Should it should be uh what's the name of the hero in Big Hero Six? Um Bay Max, sorry.

SPEAKER_04 51:57

Oh, I I great.

SPEAKER_11 51:59

We can put the He's the he's the like floating white, like he's like the robot.

SPEAKER_04 52:03

Oh gosh, I can't say I've seen it.

SPEAKER_11 52:04

Oh, you've never seen Big Hero Six? Oh, you gotta see it. Okay. It's lovely. Okay. It's really lovely. It's one of those things where it's like it's a kid's movie, but not.

SPEAKER_05 52:10

Okay.

SPEAKER_11 52:10

It's really lovely. Excellent.

SPEAKER_05 52:12

So we we put the superhero or we dissociate superhero cells. Um and so when we start out, we put them in 3D. I mean, I'm I'm gesturing this, like this big, it's really like microliters, but um we put them in 3D and they start out kind of bald up.

SPEAKER_11 52:26

It's just the endothelial cells at this point. Well, no parasites, no astrocytes.

SPEAKER_05 52:29

We put them all together. This is like the same thing. We dissociate endothelial cells, we dissociate astrocytes, we dissociate parasites.

SPEAKER_11 52:34

And you're and all from enduros pluripotent stem cells. You've they've they've all been, and they're the specific cell types that are found in blood reverse. Okay.

SPEAKER_05 52:40

Yeah.

SPEAKER_11 52:40

Yeah.

SPEAKER_05 52:40

Dissociate them, put them together in 3D, and over the course of about five days, those cells start kind of growing out in 3D. The same way that if you were to passage them on a two-dimensional plate, they would attach to the plate and kind of grow out.

SPEAKER_11 52:54

Wait, grow out? They like make others?

SPEAKER_05 52:56

No. Um, well, they do uh they can divide, but um, in this case, they start from this kind of um yeah, unhappy uh state when we dissociate them from 2D, and they just sort of start uh Wait, they literally ball up like armadillos? Yeah.

SPEAKER_11 53:11

When you the cells do without exploding or imploding or dying.

SPEAKER_05 53:16

Yeah. What? They I mean they don't like to be passage, but that's a very common technique in a cell culture.

SPEAKER_11 53:21

But the cytosol, like it becomes like a little sphere.

SPEAKER_05 53:24

I guess they don't press too much. They just are since they're in 3D, they they kind of ball up and then they start to grow out. And that's when they start moving, you know, they're not moving, you know.

SPEAKER_11 53:36

Which is just like which is just like it just expands, like the cytosol just sort of expands. Yeah. Like picture an amoeba like reaching out a foot kind of thing.

SPEAKER_05 53:43

Yeah, very subtle, but they start to move just enough so that they can find each other and link up to form vessels.

SPEAKER_11 53:50

Do they actually I'm sorry, this is this is like so do they actually like do they actually move or is it or is it like here's this thing, and it can and it can sort of relax itself, and then when it does so, the the cytosol can be can like you know, the cell wall can sort of like be, you know, can like go to this direction some more. Yeah or this direction some more. But you're talking about like I mean it's gotta be I mean maybe it's 20 nanometers, but it's not, but like but like the cell itself, if you were to take like the whole position of the cell, it's not actually moving much.

SPEAKER_05 54:21

We think that they can move some. Well, do they move? I think just through kind of uh phytosolic dynamics uh alone.

SPEAKER_11 54:29

Like wait, they can like like they can literally like ball up internally and then and then you could it's your microtubules is you could like build pull you know, pull some of it in and then push out the other side. I think well it's like a it's like a millipede doing this thing.

SPEAKER_05 54:41

I I sure hope not.

SPEAKER_07 54:42

No, I don't know.

SPEAKER_05 54:43

It's a BBB. Um but over the course of a few days, you know, they find their neighbors, they link up, and what I think is really You really want to jump past this.

SPEAKER_07 54:51

You want to jump like they just they just sort of move and like wait a second.

SPEAKER_05 54:54

They should say a microglia do, right? They're they're always sampling their environment, right?

SPEAKER_11 55:00

And so they're trying to Do they ha is that all through internal cytosolic re-architecture change? Um and they actually move through physical space?

SPEAKER_05 55:08

They go through, I think like through philopodia sampling. Yeah, yeah.

SPEAKER_11 55:12

Yeah. But which is more of kind of what I'm thinking, it's like the thing itself isn't really like moving, it's just sort of like stretching out.

SPEAKER_05 55:19

But you could, I mean, I suppose you could like can move, I think, more so than something like an endothelial cell.

SPEAKER_11 55:26

Wow.

SPEAKER_05 55:26

But they don't have um cilia or something like that.

SPEAKER_11 55:29

I mean certainly what like white blood cells move like crazy.

SPEAKER_05 55:32

Yes.

SPEAKER_11 55:33

Yeah, because they have to like get out and then they have to like get to the infection, and there's all kinds of things they do. Yeah, yeah. So Okay, so okay, I accept. I accept they move. Yes, okay, then they're in the goo, they're in the goo, which you had a nicer name for than goo.

SPEAKER_05 55:49

The extracellular matrix or the hydrogel. So we use a synthetic kind of hydrogel. And so they find each other, form these vessels, and through self-assembly, um, you start to have um yeah, the pericytes like come onto the vessel, astrocytes kind of extending their end feet, and it's this really beautiful system that um like self-assembles.

SPEAKER_11 56:11

Self-assembly. There's something in the there's something in the they're either they can sense each other somehow. They're like there's all kinds of signaling that like this is where I'm supposed to be. Yeah. Wow. Crazy. Yeah. Um and so then you end up with oh like just one, like a three, a three cell layer. Do they do they can they actually arrange into like functioning blood vessels? Like they arrange, they arrange all the way into tubes.

SPEAKER_05 56:39

Yes, that's what I mean by they they form yeah, hollow uh centers. So we can flow things through those tubes.

SPEAKER_11 56:45

It's not just the three layers that self-assemble, it's actually the whole tube self-assembles. Whoa.

SPEAKER_05 56:50

Yeah.

SPEAKER_11 56:51

So how big can you make?

SPEAKER_05 56:53

How big? Yeah. So the question actually is how small can we make those? So uh it's easier to make bigger vessels. Um, but that's been a real challenge in the field, is that how can we make capillary blood vessels that are truly capillary blood vessels on the order of what?

SPEAKER_11 57:09

When you do it in the astrogel, they make a bigger they like when they self-assemble, they self-assemble as a larger, as like a larger diameter tube.

SPEAKER_05 57:16

Well, if you use the right cells, if you are making capillary endothelial cells, those brain like muscular endothelial cells.

SPEAKER_01 57:22

And why would we do it with anything else?

SPEAKER_05 57:24

Yes, only VMAX. Um, and use, you know, the right cell proportions and the right hydrogel, then you can guide um, you know, we can move the diameter down to this capillary level. Uh, if you use a different cell type, like uh uh huvex or human umbilical vein endothelial cells, huvex, people use those because they're easy to get. Um, those form bigger vessels just by default when you put them together and you give them the right soluble factors, versus you can bias towards a smaller uh vascular diameter, and that's what we want. So we want small capillary vessels to most closely match what's in the human brain.

SPEAKER_09 58:01

Yeah, yeah. Which is how close are you?

SPEAKER_05 58:04

We could do better. We could always do better. But I think on average, around like 15 uh micron diameters, and we're aiming for like seven to ten. In contrast, most existing models, if they're doing this kind of 3D self-assembly that I'm describing, they're around 50 microns.

SPEAKER_08 58:22

Oh, it's like significantly different.

SPEAKER_05 58:24

Yeah.

SPEAKER_08 58:24

Yeah, yeah.

SPEAKER_05 58:25

So we're pushing down instead of pushing up on the diameter.

SPEAKER_11 58:29

Are you to the place where you can where you're using the tubes that are created, you're using the like tubes that are created to do studies? Yes. Yeah? Yeah. Even though it's not quite as small as you want it.

SPEAKER_05 58:41

We're we're we're re-optimizing kind of the set the system setup here now that I've started, as well as we're thinking about how we can use this model system to answer certain questions.

SPEAKER_11 58:52

Yeah, yeah. What are you doing?

SPEAKER_05 58:54

All sorts of things.

SPEAKER_11 58:55

Yeah, yeah.

SPEAKER_05 58:56

Um, I think, you know, we already talked a bit about the delivery challenge. Of course, we want to figure out, you know, the design rules that would allow us to a priori design something that will get into the human brain. Um, we also want to see um what shouldn't get into the brain that might be getting into the brain. So thinking about different environment, uh, environmental toxicants and how those impact not only if they pass the blood-bury barrier, but how do they impact the integrity of that barrier?

SPEAKER_11 59:25

What's the name of the um I jump right to um scrapie to uh what's the name of the dementia that you when you when you eat brain that has it, you get it. You familiar with this? Um it's a very speci and it's like is it it's oh they're called there's a it starts with a P. There's a specific name for the protein. We've got prion like there it is, prions, yeah, prion. Yeah, yeah. I immediately think of prions. Yeah, because you ingest them.

SPEAKER_05 59:56

Yeah.

SPEAKER_11 59:56

And so they must, but then they must get into the brain.

SPEAKER_05 59:58

Yeah.

SPEAKER_11 59:59

Right? Yeah, yeah, yeah.

SPEAKER_05 1:00:00

Yeah. So you can imagine all sorts of things in the blood that we do not want to get in the brain. You can imagine things that are in our blood that were not in our blood decades ago based on just environmental microplastics, microplastics, nanoplastics, other chemicals, not just the plastics themselves, but the um, you know, the emulsifiers that are leaching out of those plastics. So, how do all of those things impact our blood-brain barrier? Yeah. There are lots of questions.

SPEAKER_11 1:00:26

Um, I go to I jump right to Rome and and and and I and pipes that are made of iron.

SPEAKER_04 1:00:33

Yes.

SPEAKER_11 1:00:33

Not lead, sorry. Yeah, pipes and pipes that are made of lead. It was actually, I was at, so I went to um, I was in Rome and I asked I we were doing a tour of the um the Coliseum and the tour guide was amazing. So at the end I was like, what's the coolest thing that like people don't know about? She was like, here's what you have to do tomorrow. And they hadn't opened it yet. So we were literally the first people who did it in like um they had just opened up Livy's house, Augustus' wife. They had spent they had yeah, right up on the Capitoline Hill. So they had spent um like years restoring this. Um we were like the first people to walk through it as tourists. Um, and one of the things they had was they had like, and these are the pipes. And I was like, tell me if they're lead, and they and the three guy had no idea. I was like, come on now. Like probably lead. Yeah, yeah.

SPEAKER_03 1:01:20

If they were restoring this thing.

SPEAKER_11 1:01:22

But so it's like that's immediately what I think of as like, is like, what are we doing that we don't know that we're doing?

SPEAKER_05 1:01:27

Right. And so I think that's the thing is we can look back and think, oh, I can't believe that people, you know, a decade ago were doing this thing. And what is that thing that we're currently doing today that we're you know exposing?

SPEAKER_07 1:01:42

There's plenty of those that are very outright and obvious. Yeah.

SPEAKER_05 1:01:45

There are plenty of them. We don't know for you know, just the stuff of you know, we don't know quite yet. Um and oftentimes we replace things and say, oh, this is free of this cap goal. Well, what did we replace it with? Yeah. Has that been tested? Yeah.

SPEAKER_11 1:02:01

So yeah, yeah, yeah. Well, it's got no BPA in it, but yeah, what did we replace that with? Yeah.

SPEAKER_05 1:02:06

So there are lots of questions. And, you know, I'm working on the blood brain barrier. I'm very, you know, passionate about that work, but recognizing the need for other model systems like the um the placental barrier, I think, is a really important area of research too. And that's just, you know, an example. We need to be thinking about how um, you know, our own organs and our children's organs would be exposed to these types of uh changing environments.

SPEAKER_11 1:02:31

I'm super curious. I should come up with a question, but I'm gonna come up with something off off the top of my head.

SPEAKER_04 1:02:36

Okay.

SPEAKER_11 1:02:36

What's your favorite like aha moment? Wait, wait, wait, wait. Of a of a of an experimental result you had where you were like had been working on something and then you got the result and you were like, oh my God.

SPEAKER_05 1:02:50

Yeah.

SPEAKER_11 1:02:51

And it can be so many. I mean, right. What's the first one that jumps to mind? It doesn't have to be about anything we've been talking about.

SPEAKER_05 1:02:57

Yeah. I mean, it might just be about what we've been talking about. Um, going back to that lipids discussion, the first time that I made the particles synthetically, um, and I exposed cells that were loaded up with lipids. I exposed them to these particles and it kind of flushed out those lipids. I was just looking at the microscope and like, oh my gosh, it worked.

SPEAKER_11 1:03:18

And you could, oh, and it was big, you could actually watch like it's microscope scale. So you weren't, you weren't like, what a cool mass spec result, right? Like, yeah, you could actually like see a cell like full of lipid particles and like watch it leave.

unknown 1:03:30

Yeah.

SPEAKER_05 1:03:30

And so that's so cool. And then you you have that moment and then you think, well, it could have worked for all of these other reasons. So now I need to run like a hundred controls. And even after that point, it still seems to be working. So that's this idea of like what I love about science is the aha moment, but then also the skepticism of like, yeah, you know, let's go back and really make sure that it's working the way I think it is, as well as under trying to understand the mechanism of why it's working. So that's been a lot of people.

SPEAKER_11 1:03:56

Did you love Legos when you were a kid?

SPEAKER_05 1:03:57

I loved Legos. How became that one?

SPEAKER_11 1:04:01

That's so fantastic. No, that's not true. No, no, it's it's the it's the engineering. It's it like it's that the the uh it's like there's a like here's a psychiatrist for me. There's a very young part of you, right? Like there's a child part of you that just like loves the engineering. Yeah, it's like, yes, we're gonna build something and that's cool. And I that is what I'm going for, but also like the process of I just want to put this brick and this brick, and we're gonna get this other brick, and what's it and we're gonna get this other brick, right? And it's just so enjoyable, right? Yeah, yeah.

SPEAKER_12 1:04:29

Did you also love Legos?

SPEAKER_11 1:04:30

I did not. Really? No, I never have. No, no, I'm not an engineer. Interesting. Yeah, that's why I'm a doctor, I'm not an engineer.

SPEAKER_03 1:04:37

I guess I just kind of assumed everyone loved Legos as a child, but I live in a very uh That's why, that's why like I like I love science.

SPEAKER_11 1:04:44

I love it, but I love I love learning about it. Um I love the ideas. Um, but the actual work of like now we're gonna pipette 4,000 more times over the next two months. We're just gonna keep on pipetting. Yes. That's what we're gonna do, right? Like I just I it doesn't somehow it doesn't, it's not like we need all kinds of scientists, uh all kinds of thinkers. Yeah, well, I suppose I suppose I have sort of achieved it somewhat in my field, but um but it's different. Yeah, yeah. The lab thing is its own thing.

SPEAKER_05 1:05:17

Yeah. It it is interesting now with this position. Um, I've just been, you know, very busy with everything uh that being a professor entails. So I've been less in the lab, far less in the lab. Yeah. And it's been an adjustment because yeah, through my PhD and but it's fun. Yeah, about different scales of science.

SPEAKER_11 1:05:37

You're like six, eight months in?

SPEAKER_05 1:05:39

Uh six months.

SPEAKER_11 1:05:40

Yeah, six months in. Yeah, and you're and you're you're transitioning to leadership and to and to team organization and to funneling young people through, right? It's the team members that how much of your like the role of the professor is so much less do the science. And it's so much more like pick the students and bring them the funding. But they're the ones doing this right. And you like sort of be like, maybe you should try this when they're, but it's a but they're the ones doing it because you're because you're doing all this organizational level stuff.

SPEAKER_05 1:06:08

It's interesting to know that that that transition wasn't so far ago. It was um, I mean, it's often attributed to Ernest Lawrence um uh during World War II, like move of big science, where the PI's role, the professor's role is to secure funding to then have a team uh at the bench doing things.

SPEAKER_11 1:06:30

Yeah, because of course, because like because um Ramoni Cajal is like he's the one doing the drawings. Yeah. You know, Freud did that too. Freud's first scientific like publication was neuronal drawings, was drawings of neurons that were so good that they actually are like still, they were like some of the best. Yeah, yeah, yeah.

SPEAKER_06 1:06:46

Yeah, so it really moved away from that. Yeah, of course. And that like when so how did that that was a post that was post-World War II.

SPEAKER_05 1:06:52

Or during.

SPEAKER_06 1:06:53

Huh.

SPEAKER_05 1:06:53

That's my understanding. Yeah. So I think that this idea of the professor having to go out and fundraise to support science, it was really an American um scientific uh uh choice rather than you know, in the old older laboratories in in Cambridge, for example. Yeah. Um they were much more of like the professor was at the bench doing experiments. So that was a moment of uh uh And the students were also how but the students were also in the lab too.

SPEAKER_11 1:07:22

Didn't the professor then also still have to do the like administrative work and have to do that?

SPEAKER_05 1:07:28

But it wasn't that the professor's main role or the role that takes up a lot of their time was fundraising. Yeah. And that was a distinction. Yeah.

SPEAKER_11 1:07:36

So where do they get the funding?

SPEAKER_05 1:07:38

Um, I mean, at that point, I think we were in the war, so uh government funding, I believe.

SPEAKER_11 1:07:44

So I mean, like if you don't fundraise, how do you have funds?

SPEAKER_05 1:07:47

Oh, I think it's uh kind of default supplied by the government.

SPEAKER_11 1:07:52

Oh, I suppose, or yeah, or it's just like part of the the university's uh foundation or something. Yeah.

SPEAKER_04 1:07:59

Yeah. So anyways, here we are.

SPEAKER_11 1:08:01

One of the earliest the earliest model I can think of for that is um is uh the March of Dimes. Are you familiar with um the how cancer research began in this country?

SPEAKER_04 1:08:13

Uh no.

SPEAKER_11 1:08:14

Dana Far like Dana Farber Institute and that kind of stuff.

SPEAKER_04 1:08:17

Somewhat for I mean, I know the now, but um what what was the So you're so you're familiar with the term March of Dimes?

SPEAKER_11 1:08:24

I am familiar with the. But you probably have no idea what it is. Right. So um and I'm really curious when it was. It had to have been the it might have been the 50s, but it might have been the 30s. Um I'm I I want to say it was pre-war, but I'm not sure. Um where I'm forgetting his name, but there was a doc who was just this sort of standard, like very type A, like gonna go do it. Um and he was gonna solve cancer. He was like, that's what he was gonna do. And he figured out, um, and he and he needed funding. And so a huge part of what he did, and a lot of the like the reasons, the reason like so much in Boston, right? Um is he found, he was a he essentially was a came up with ways to market. So it was things like um he he took like he was like, okay, well, let's do pediatric cancer because that's a thing that people like feel was so awful. We're gonna stop that from happening to children, right? And it was he was looking at all kinds of things, but like that's the thing that'll get people to. And there was a um a poster that they did of like save Jimmy.

SPEAKER_05 1:09:27

Isn't Jimmy not real a real person?

SPEAKER_11 1:09:29

Jimmy was well, no, he was a real kid, but he didn't have cancer.

SPEAKER_05 1:09:32

Oh.

SPEAKER_11 1:09:33

He was just like he was like a it was like a model they used.

SPEAKER_13 1:09:35

Wow.

SPEAKER_11 1:09:36

Yeah, but Jimmy, like, but Jimmy was a like, I'm pretty sure there was a real kid that they took pictures. It just was um and they were like, Jimmy needs help.

SPEAKER_12 1:09:43

Yeah.

SPEAKER_11 1:09:44

Um, I don't think they fully invent, but it might have been far enough back that's like readers digest and there aren't actually pictures. Um, but I think there were pictures. Um and the March of Dimes was uh a donation tactic.

SPEAKER_10 1:09:56

Okay.

SPEAKER_11 1:09:57

Right? We're not gonna ask you for a lot of money, right? Instead of trying to get a ton of money from the Rockefellers or or and a ton of money from the, you know, the Vanderbilts or whatever, we're just gonna ask, we're gonna we can convince all these people that Jimmy needs help. And you can just give us a dime. And of course, it was a time when people had money in their pockets. And so that's the like, and that was the whole idea of there's a there will be a you know, it's also like got that war feeling to it, right? Where we all together are gonna march to the that's the march of dimes. And it worked. It like made it it created an entire, yeah, yeah. But but it also that's like he's the physician, but he's very much the marketer. He's very much, he's like organizing a larger, it's there's this thing that happens self-assembly, yep. Where it has just become apparent that larger systems have more put can do more, right? And so initially people are guessing and like discovering that, and the ones that land on it and are good at it end up having so many resources that they can direct them, but then it just becomes clear that that's the way to so here we are. Yeah, wow, it wasn't like that before. Huh.

unknown 1:11:05

Yeah.

SPEAKER_11 1:11:06

Do you miss it?

SPEAKER_05 1:11:07

I mean, you do I didn't experiment.

SPEAKER_11 1:11:09

No, right, but I mean I guess you said you do miss it. So I do miss it being at the bench.

SPEAKER_05 1:11:13

But at the same time, it is fun to see the new students come in and learn those experiments and hopefully have those alpha.

SPEAKER_11 1:11:20

Yeah. Yeah. Well, and you'll still get to like I get to live vicariously. You'll ha instead of having just your own two hands, you'll have dozens of hands.

SPEAKER_05 1:11:28

And really smart and curious and excited students. So I think that'll be very it already has the Yeah.

SPEAKER_11 1:11:36

You're not I'm I'm a little older than you, and I already have kids, right? You're not old enough yet to be tired. Right. But there's also this like youthful energy thing that they have, and it's like a it's like, oh my god, like it's really good that you have that much energy because I do not have that much energy anymore. Oh my god. Yeah. Well, this has been super fun.

SPEAKER_03 1:11:56

Yeah, thank you.

SPEAKER_11 1:11:57

Yeah, thanks for doing it.