Why a nasal spray changes the game

1:47:11funny how epigenetics plays an increasingly more important role as we get deeper into the understanding of these systems. >> Exactly, yeah. And one more thing that I want to touch on with this paper is they ask the question, well, where are these cells interacting? I think you're going to like this one >> Okay. because there's a cool mechanism about how they actually did the science and then what they actually found out. >> Okay. Okay? So, the question is where are these immune responses actually happening? Okay? So, usually when you want to answer that question, what you do is you take a bunch of lung tissue, you put it into a blender, and then you run some transcriptomics and you try to

1:47:52figure out what part of the genome is being read. When you say a blender? A little yeah. >> Okay. Yeah, yeah, yeah, you just >> Yeah, you just mix it up. >> Okay. Then you put some transcriptomics stuff in it which tells you like what part like what is the mRNA profile. Got it. Right? But because it's in a blender now you don't have any of spatial Yes. >> You've lost all of the spatial information. >> Yes. Right? What we'd want to do is try to figure out where the genes are being transcribed. Like in a tissue, I take a slice of lung, let's say, from my mouse, and I want to figure out where is the immune response happening geographically. >> Yes. Okay. Yes. So,

1:48:34they use the technique called phenocycler fusion. It used to be formally called codex for a spatial proteomics. Here's the idea. Okay, so normally what you do is you want to figure out where the proteins are, right? Where specific proteins are. So, you make an antibody that is tailored to stick to that particular protein. It sticks to that particular protein. Each of these antibodies has a fluorescent dye on it, so it's going to glow in the dark in some sense. So, if we look at the photo we have here, each of these antibodies is tagged with a fluorescent dye. Each of the different colors tells us what different antibody there is, and

1:49:14there you go, you've got a geographic map of where the stuff is. Now, you're limited to mostly like four or five different colors though. Okay. Right? Because you don't have that many dyes. You don't have that many lasers. So, what if we want to do like hundreds of different types of proteins? How am I going to actually do this? Well, with Codex, with this PhenoCycler fusion, here's what we're doing. The antibody is actually not attached to a dye. It's attached to a piece of DNA. Okay. Okay? Each different type of antibody is attached to a piece of DNA. Then, we have another piece of DNA

1:49:55that is complementary that is attached to a dye. And so now you have a barcode and you have another barcode. Do you already see it? It's so nice. Okay, so here's what we're doing. Here's Here's what we're going to do. >> This is good. Right? The antibody is attached to a DNA. I have another piece of DNA that latches onto that DNA. It's complementary. Just the the A becomes a T, C becomes a G. That attaches and that has a bit of dye. Okay? So, when I'm like looking at a Where's Waldo type book, right? And let's say I want to find all the people with red hats.

1:50:35I have a little thing that says attach to the red hats and then I take a picture. Then, I wash it out and this is the next next photo I think you will see. Yes. This is the cycle. I attach, I take a photo, I wash it out, I attach with another barcode, I take a photo. The key is I can take a photo with the same color of light. But, because the anti because the primer is being attached at different locations, I now have a snapshot at every given point. And so I can expand the number of proteins that I can actually image. >> Right. Because you're you're no longer limited by the number of dyes and lasers

1:51:17you have. >> Yeah. Because the mechanism to make the connection is now this one part of DNA connected to the other part of DNA. On the other side of it, it can have a whole range of stuff. That's It's such a nice idea. It's only in the last 5 years. This was also developed at Stanford. This is very clever. >> This is a very clever technique, I have to say. >> Yeah, no, that is that is that's quite nice. Cuz it's it it feels non-obvious >> Yeah. as a choice. >> Yeah, but then once you like think about you're like, "Oh, duh." Yeah. >> Yeah, yeah, yeah. Yeah. That's why I literally for those who are listening and not watching me, when you said after you almost got through the second or third sentence, I almost fell out of my chair cuz I immediately understood what they >> Yeah, I was like, "Oh,

1:51:58come on, it's so obvious." >> Yeah. Yeah. But why have we not >> It's so nice. >> Um but it always takes one. >> yeah, and so here's what they found with that. Okay. What they actually found when they looked at these lungs, they found with spatial imaging tertiary lymphoid structures. Here's the idea. Usually, when it comes to this um adaptive immune response, the antigen has to go to a lymph node. It's got to get integrated there. The T cells has to recognize and then it's got to come back. This is going to take weeks. Okay? What they see in the lungs of these mice is that the immune cells are rapidly congregating and building up pop-up makeshift lymph nodes.

1:52:40Like on the battlefield, they're doing management and creating like little I don't know. You know what I mean? >> yeah, yeah. Yeah, they have these outposts at specific areas on the battle front. >> On the battlefield in the lungs themselves. >> that are relevant to the >> have to go all the way back to the lymph nodes to figure out So so in this analogy, if you have a central if you have a central command that has like houses the core intelligence pieces, what you're What's happening is we're actually getting these satellite outposts that have uh localized intelligence and relevant information. So that people who are nearby don't need to wait because they already have

1:53:22basically, you know, preloaded not preloaded but they already have the relevant information that people those that are nearby are able to access without waiting for the signal to come back from central command. Tertiary, what was it? Tertiary lymphoid structures. >> Yeah, lymphoid is the the lymph nodes are like uh organ system that coordinate the immune response. And here that organ system is now creating little tiny outposts. >> Yeah, yeah, yeah, yeah. Yeah, all which which again if we look at just like military tactics as a reference point. >> so it like maps out almost perfectly. >> kind of crazy. Dude, that Yeah. >> of crazy. Yeah, it is kind of crazy. It

1:54:02is kind of crazy. The one that I I got really kind of excited about was the idea that it could actually like help allergies and allergy asthma because um it turns out that allergies are basically a maladaptive response to harmless allergens, right? It's like the immune system just kind of going What's going on? What is this? What's going on, right? But this particular vaccine it's designed to aggressively bias the immune system towards antiviral sort of innate immune response rather than like oh I recognize something that's bad. And the vaccinated mice, so on the left you see naive mice that are control, in the

1:54:43middle you see unvaccinated mice that are part of this HDM challenge, which is effectively you're introducing like an allergen to them. You see lots of mucus build up, right? In the middle. On the right hand side it looks more like control. It looks like I don't got a stuffy nose. Yes, that's exactly right. So it's actually like sort of calibrating that I response as well. I mean, I think this is huge, right? Because it's First of all, it's a completely different way of trying to understand how vaccines work and how to implement vaccines, right? Right? It's no longer a lock and key mechanism. It's literally just saying we're just going to prime the immune system to be on high alert. And for something

1:55:26like a pandemic that's happening in the future, it's going to happen in the future, yes, right? There's a pandemic There's a pandemic coming. Um this can be kind of a stopgap because imagine there's a pandemic that comes out of wherever, you can fly out these vaccines that don't need a sequence of whatever pathogen there is. I don't I don't need to know what COVID-19 is or what COVID, you know, I don't know, 2027 is. I can just fly out these vaccines and whatever health care worker is going in there or whatever, they're just their immune system is going to be primed for whatever random