The real target: making the lung itself a stronger fortress

1:40:03If every time some random crap comes in and we have an immune response, it's not going to be good. It uh it has a um what do you It has an asylum program. Yeah. Yeah. Yeah. Yeah. In some sense. It's not a strict border where you can't cross the border. >> Because that would be completely unreasonable. >> Right. So, it's like, "Okay, what's your case?" >> Yeah. Exactly. Yeah. So, now let's look at the cells the immune cells that are respon- that are responsible here. There's tissue resident immune cells, which are the tissue resident memory T cells. These are tissue resident, meaning they hang out in the lung. Mhm. Okay? Then, there are these things called the alveolar macrophages. These are macrophages, so there's These

1:40:44are innate immune cells. These are the beat cops, the infantrymen. Mhm. They hang out in the alveoli. They were discovered by Élie Metchnikoff in the 1880s. He won the Nobel Prize in 1908 for it. They basically hang out in the alveoli, which are these compartments that interface between the blood and the outside world. >> This is I mean, it's like literally the border. >> Yeah, they're the they're the border. Yeah. >> Yeah. In some sense, right? >> Yeah. Yeah. Yeah. And in the past, we used to believe that the memory T cells, which are our special ops, >> Yes. they remain dormant until there's a specific target antigen that reappears. But, the data from this particular paper

1:41:26shows that there's actually a radically different dynamic. The when we when when you put that nasal spray in, those tissue resident memory T cells, they actually broadcast training signals to these infantrymen. Interesting. Alveolar macrophages. So the the special operations people actually have an active channel of communication at the beginning of the inciting incident. Initially, the thought was the inciting incident happens, the infantrymen, the the innate immune cells respond. There's no communication happening necessarily.

1:42:07But then because they're losing the battle, then we bring in the big guns. But actually, what we're sort of seeing or saying here is the special ops, uh, the adaptive immune cells >> by that nasal spray. Right? And so now they, because they got primed by the nasal spray, they're already pre-sending information to the border, where we have these innate immune cells to say, "Hey, be on alert. There might be a caravan coming through." Yeah. And because of that, it actually makes the effective response better. Yeah. But I still, okay. Let me Let me wait. And so the question is, okay, how does that dialogue

1:42:47actually happen? That That was my question. Right? Like how how are you talking to one another? Well, the dialogue happens from something called RANKL. They actually identified what this is. This is the receptor activator of nuclear factor kappa B ligand protein. Okay. Okay? This is a protein. These T cells broadcast high levels of this protein. Okay. And the crucial proof was if you were to block this pathway, you were to block this protein, this antibody, the antibodies would completely vanish. >> Mhm. This response was completely not there. So so so if when this was present, this RANKL, when present, the antibodies

1:43:29would generate and form and it's totally fine. Yeah. When it wasn't present >> artificially take it out. >> Right. Right. Then the there's basically a delayed or no response. >> Yeah, exactly. And so what you're actually doing effectively is you're teaching these macrophages, these infantrymen, new tricks >> Mhm. in some sense. So now the question becomes, well, how are you doing that? >> Yes. These macrophages I thought, you know, they're they're kind of dumb in innate immunity. How are you training them to be immune and really select certain things and like and like become this more effective cop in some sense. Well, it turns out that they acquire biological memory not

1:44:11through genetic recombination, which is what we get from the special ops, but through epigenetic reprogramming. What's happening is you can imagine in epigenetics, right? Um your entire cellular genome is like a library. All of your DNA is like a library, but it's massive. And every single cell is specifically only reading certain books, right? Only certain parts of the genome are actually being expressed in certain cells. Now, a vast majority of these books are tightly shut through epigenetic markers. And what ends up happening is there are proteins

1:44:51called histones that wrap around segments of DNA that they don't want the cell to look at. What's happening with these particular macrophages is that level of books being shut and open is being changed. There's two types of chromatin. There's heterochromatin and euchromatin. Chromatin is like our DNA. Heterochromatin is all of our DNA that's being packaged up so that no one can read it. Euchromatin is kind of the histones are spread out and you can actually read the DNA and make proteins out of that DNA. >> It's like an encrypted versus a non-encrypted messaging channel.

1:45:32>> That's exactly right. And what they could see is that the RANKL signaling was unspooling the DNA Mhm. >> and making parts of the DNA more visible. I It was left out in the open. In the like in the context of like a heterochromatin heterochromatin becoming more like >> More euchromatin. Exactly. And very specific parts of that DNA >> Mhm. were becoming more accessible. Mhm. Meaning like certain books in the libraries which had good things in those specific books. >> Yes. Like how like how to identify stuff. How to be a better cop. >> That's actually fascinating. Yeah. Oh man, that's really good. >> Yeah. Cuz because you can you can sort of like it kind of makes sense

1:46:14where it's like you don't too much information is going to overload any system. And so you have to be selective about what information is displayed to what part of you when. And that coordination problem at the level of the body is orders of magnitude. Yeah. >> Like because of the number of constituent parts and Mhm. combinatorial pro like the processes that stack on top of each other. I like it makes my head hurt. >> Yeah. Yeah, there's there's too much, right? Um and it it's just pretty cool that we could like get down to this level >> That's crazy. >> of chromatin remodeling to understand it, you know? Is isn't epigenetics still something as a concept

1:46:55>> Mhm. that is in its infancy? Very much so. Compared to like like DNA, for example. Yeah. So I think it the reason it's fascinating to me is you know we're continuing to chip away at the understanding and it's it's it's