WEBVTT 00:00:03.497 --> 00:00:10.497 This is the Convergent Science Network podcast. Leading researchers in the domain 00:00:10.497 --> 00:00:16.777 of neuroscience, brain theory and technology are interviewed by Paul Verschoor and Tony Prescott. 00:00:20.377 --> 00:00:25.757 So this is Paul Verschoor with the Convergent Science Network podcast for the 00:00:25.757 --> 00:00:30.337 Barcelona Cognition, Brain and Technology Summer School of 2018. 00:00:31.777 --> 00:00:36.097 And I'm here with Joram Vodovic. Welcome, Joram, to our summer school. 00:00:36.217 --> 00:00:44.657 You spoke about the inflammatory response, inflammation, and also how the body responds to that. 00:00:45.257 --> 00:00:54.077 So how do you think the notion of inflammation is informative with respect to 00:00:54.077 --> 00:01:00.017 questions around, let's say, control and how even the brain might be engaging with the body. 00:01:00.637 --> 00:01:08.637 Well, thanks, Paul. I think that at some level, it is just natural to think 00:01:08.637 --> 00:01:13.777 about that a process that can be as destructive as inflammation needs to be controlled. 00:01:13.957 --> 00:01:25.297 So the organism is wired to be able to respond to cues to cues that can be dangerous 00:01:25.297 --> 00:01:27.057 with an inflammatory response. 00:01:28.137 --> 00:01:33.597 And maybe even cues that are just stressful. And then that has to be resolved 00:01:33.597 --> 00:01:37.877 and reset and be available to be used again. 00:01:38.297 --> 00:01:45.957 And so one thing that's interesting that we find is that inflammation is regulated 00:01:45.957 --> 00:01:49.457 at a very local level, at the cellular level, 00:01:49.537 --> 00:01:55.397 that does not immediately appear to require any kind of additional neural control. 00:01:55.517 --> 00:01:59.477 But at the same time, when we look structurally at the way the neural mechanisms, 00:02:00.417 --> 00:02:09.177 all evidence points to pathways regulated by the vagus nerve that are probably 00:02:09.177 --> 00:02:14.037 involved in sort of minute-to-minute regulation of inflammation, 00:02:14.417 --> 00:02:17.877 to the point that you can actually target that 00:02:17.877 --> 00:02:23.017 mechanism to uh improve or 00:02:23.017 --> 00:02:26.697 reduce the inflammatory response in uh fairly 00:02:26.697 --> 00:02:32.817 intractable inflammatory disease states in a way that's much more powerful and 00:02:32.817 --> 00:02:38.137 potent than simply administering drugs uh systemically with that now you you 00:02:38.137 --> 00:02:43.777 only jump to the conclusions before we you even have done the introductory parts, right? 00:02:43.837 --> 00:02:51.617 Because also in your talk, you indicated that in your view, inflammation is underlying the. 00:02:52.576 --> 00:02:56.756 Maybe all diseases or is involved in all diseases in some form. 00:02:56.976 --> 00:03:04.496 Yes, I think so. So it's very global, but would it also mean a very nonspecific 00:03:04.496 --> 00:03:08.596 reaction of the body to a pathological perturbation? 00:03:08.596 --> 00:03:14.636 I think one way to look at it in a kind of integrated way is to say that everywhere 00:03:14.636 --> 00:03:22.576 and all the time in the body, we need to respond to stressful or noxious or infectious stimuli. 00:03:23.056 --> 00:03:31.196 And that because we are wired to do that, it's possible sometimes that those 00:03:31.196 --> 00:03:36.596 control points will be insufficient or will be overly robust. bust. 00:03:36.696 --> 00:03:40.596 And then that may be the real basis of inflammatory disease, 00:03:40.736 --> 00:03:44.736 or maybe all disease, if all disease has an inflammatory component. 00:03:44.976 --> 00:03:52.876 So in a sense, we can make the argument that it's failure of control that is 00:03:52.876 --> 00:03:54.456 what makes inflammation bad. 00:03:55.176 --> 00:03:59.136 Because within a range, inflammation will stay local. 00:03:59.516 --> 00:04:02.776 And when it stays local, it generally does what it's supposed to do. 00:04:02.776 --> 00:04:08.356 It's possible for it to become overly robust locally to a point, 00:04:08.416 --> 00:04:14.876 but most of the time that is still compatible with reasonable organism health. 00:04:17.413 --> 00:04:22.933 The hypothesis would be that once either the stimulus is too prolonged or too 00:04:22.933 --> 00:04:30.533 big or that there is a genetic variability that makes one over responsive or 00:04:30.533 --> 00:04:34.733 under or in or unable to control sufficiently well. 00:04:34.733 --> 00:04:39.193 Well, now inflammation spills over into the systemic circulation. 00:04:39.633 --> 00:04:47.453 And that's typically when we would say, this is a bad, this is a disease, this is a bad outcome. 00:04:47.453 --> 00:04:55.233 And so then, of course, the corollary to that is that it is the brain and neural 00:04:55.233 --> 00:05:05.313 circuits that are now failing at their job to keep inflammation localized. 00:05:06.133 --> 00:05:10.473 We don't know yet whether this is neural. We don't. Because in some sense, 00:05:10.533 --> 00:05:14.053 we didn't even get to the point that we really defined inflammation. 00:05:15.113 --> 00:05:18.593 What does inflammation actually really mean? Because in some sense, 00:05:18.653 --> 00:05:23.233 it seems to be a phenomenon that is deviating from the standard, 00:05:23.493 --> 00:05:30.473 but it can occur at many different spatial temporal scales and also with varying levels of intensity. 00:05:31.233 --> 00:05:35.013 So how do we now really define inflammation? What's inflammation exactly? 00:05:35.553 --> 00:05:41.793 So at a core level, I keep using the phrase that inflammation is communication. 00:05:42.733 --> 00:05:48.213 So I think inflammation is an intermediate set of pathways that connect the 00:05:48.213 --> 00:05:56.333 original insult or injury or deviation from homeostasis to some response to that, right? 00:05:56.453 --> 00:06:00.193 So of course, the typical control systems you're thinking of are neural control 00:06:00.193 --> 00:06:03.093 and you're thinking of the nervous system as having that function. 00:06:03.953 --> 00:06:07.653 It probably happens on a faster timescale than what inflammation does. 00:06:09.294 --> 00:06:12.414 So inflammation is the communication framework, but now the problem is that 00:06:12.414 --> 00:06:18.114 the language of that communication can itself become the cause of the disease 00:06:18.114 --> 00:06:23.214 or the aspect of the disease that becomes propagated or gets worse or cascades 00:06:23.214 --> 00:06:25.014 further and further out of control. 00:06:25.234 --> 00:06:31.234 So inflammation has this dual role, or you could argue that it's an intrinsic role. 00:06:31.234 --> 00:06:40.614 The very fact that it's an intermediate timescale process and that it uses molecules 00:06:40.614 --> 00:06:44.534 that can cross into, say, the neural system, but also into other aspects of physiology. 00:06:44.874 --> 00:06:49.174 Set it up for this possibility that if things go out of control, 00:06:49.414 --> 00:06:55.414 the very act of communication becomes the detrimental thing. 00:06:55.414 --> 00:06:58.454 And and now you may not even be able to find any 00:06:58.454 --> 00:07:01.874 evidence any remaining evidence of the original stimulus that 00:07:01.874 --> 00:07:05.154 started the whole process the whole dominoes falling 00:07:05.154 --> 00:07:08.274 you just see the dominoes are falling right 00:07:08.274 --> 00:07:11.414 so now and now the problem becomes that it's the dominoes falling 00:07:11.414 --> 00:07:14.714 that are your problem and that's when people say this is an inflammatory disease 00:07:14.714 --> 00:07:21.814 they focus on those mediators um in fact they they often confuse or or or interchange 00:07:21.814 --> 00:07:29.014 the term marker and mediator you So as if a molecule that is there in the body 00:07:29.014 --> 00:07:32.214 is doing nothing more than to act as a marker of something. 00:07:32.434 --> 00:07:36.294 Of course it's not. It's having a biological effect. So it's a mediator. 00:07:36.354 --> 00:07:41.774 If you now bring it down to the simplest form, what's the simplest form of inflammation 00:07:41.774 --> 00:07:44.374 that would still qualify for that label? 00:07:45.294 --> 00:07:48.234 Uh i would argue the simplest form of inflammation 00:07:48.234 --> 00:07:53.514 can be seen in very primitive organisms or even perhaps single cell organisms 00:07:53.514 --> 00:07:59.714 where there's a stress response so the the response to anything like a chemo 00:07:59.714 --> 00:08:07.314 ismotic stress even a lack of nutrients or an overabundance of some some stimulus, 00:08:07.454 --> 00:08:14.734 the molecules and signaling pathways that one can find are sort of a proto-inflammatory 00:08:14.734 --> 00:08:21.514 response because those same molecules are typically implicated in doing something inflammatory. 00:08:21.614 --> 00:08:26.514 If you were to just give those molecules, you will see a response that you could argue is inflammatory. 00:08:26.954 --> 00:08:29.094 We did some of our studies. 00:08:30.114 --> 00:08:33.114 I didn't go to the lowest level organisms, 00:08:33.114 --> 00:08:36.434 but we did some studies on malaria and 00:08:36.434 --> 00:08:41.114 we were looking actually at the mosquito host for the malaria parasite and show 00:08:41.114 --> 00:08:45.094 that that mosquito host is elaborating exactly the same types of responses that 00:08:45.094 --> 00:08:50.274 the human host does right so now this mosquito that is thought of as part of 00:08:50.274 --> 00:08:54.594 the problem in the disease you know for carrying the vector for being the vector for disease. 00:08:56.205 --> 00:08:59.965 You might say, well, it's not harmed in any way, it doesn't care, 00:09:00.105 --> 00:09:02.385 or perhaps it's even benefiting from transmitting this disease. 00:09:02.505 --> 00:09:05.785 But the reality is that it doesn't. It's fighting this disease tooth and nail. 00:09:05.905 --> 00:09:09.325 In fact, the disease would be way worse if it wasn't for the fact that this 00:09:09.325 --> 00:09:13.505 mosquito has done a quite good job of limiting the parasite burden in itself 00:09:13.505 --> 00:09:16.565 before it ever bites the host. 00:09:16.705 --> 00:09:20.225 And as a separate twist, the act of blood feeding, 00:09:21.345 --> 00:09:25.305 depending on the kind of host that it is, if that host is infected, 00:09:26.205 --> 00:09:30.265 There will also be inflammatory meteors that transit into and get internalized 00:09:30.265 --> 00:09:34.045 into the mosquito, and the mosquito recycles them and uses it for its own signal 00:09:34.045 --> 00:09:35.845 transduction to fight off the parasite. 00:09:36.165 --> 00:09:41.045 So there's this entire almost ecosystem-type effect where inflammation is no 00:09:41.045 --> 00:09:45.625 longer about just what happens to the one organism, but it's about a cross-organism 00:09:45.625 --> 00:09:46.625 transfer of information. 00:09:47.665 --> 00:09:52.105 So you would see that's originating already in single-cellular organisms, 00:09:52.305 --> 00:09:54.265 so it's a very old mechanism. 00:09:54.365 --> 00:09:57.465 Yes. So it means they won't understand it. We shouldn't start looking at complex 00:09:57.465 --> 00:09:59.145 multi-organ systems, right? 00:09:59.205 --> 00:10:02.005 You should start with single-cellular ones. People are doing great studies in 00:10:02.005 --> 00:10:07.245 zebrafish, for example, because they're very amenable to perturbation and visualizable 00:10:07.245 --> 00:10:08.905 in terms of fluorescence. Should we start with E. 00:10:08.925 --> 00:10:13.605 Coli or something like single-cellular? So people have, 00:10:13.845 --> 00:10:19.805 I mean, typically what they do is then they engineer the unicellular organism 00:10:19.805 --> 00:10:24.085 to be able to record what essentially it's doing and so forth. 00:10:24.145 --> 00:10:30.345 The problem with that is that that's great if you're trying to come to the kind 00:10:30.345 --> 00:10:36.045 of evolutionary mechanisms and initial set of feedbacks and so forth. 00:10:36.994 --> 00:10:41.074 But because the problem with that approach, though, is that because we can also, 00:10:41.114 --> 00:10:45.654 because we can show that isolated cells from, 00:10:45.734 --> 00:10:50.134 say, people or mice can be put in culture and can exhibit this inflammatory 00:10:50.134 --> 00:10:55.834 response that has many features that we can see at the tissue and the organ and the organism level, 00:10:56.034 --> 00:11:00.474 the problem is that the two things aren't automatically dockable. 00:11:00.554 --> 00:11:03.294 Just because we can see it at the single cell level doesn't mean 00:11:03.294 --> 00:11:06.294 that we automatically understand the way inflammation is 00:11:06.294 --> 00:11:09.114 really really regulated because normally you will never have 00:11:09.114 --> 00:11:12.014 any of our cells just sitting there by itself it's always going 00:11:12.014 --> 00:11:15.034 to be in the environment of the entire organism so you 00:11:15.034 --> 00:11:18.214 know it's a teleologic argument are you you know maybe what you really need 00:11:18.214 --> 00:11:25.834 to understand is the entire organism and and control as a system to infer the 00:11:25.834 --> 00:11:29.014 core features that matter there and see which of those features can still be 00:11:29.014 --> 00:11:33.434 recapitulated at the individual cell But at the bottom, 00:11:33.594 --> 00:11:41.434 would it be fair to say that it is linked to the homeostatic functions of the 00:11:41.434 --> 00:11:42.354 single-celled organism? 00:11:43.494 --> 00:11:48.594 And then maybe we should limit it to the very specific homeostatic functions, 00:11:48.854 --> 00:11:54.134 the Materana and Varela called autopoiesis, which is, it is the homeostatic 00:11:54.134 --> 00:11:58.394 function that allows the self-maintenance of the organism. 00:11:58.914 --> 00:12:03.734 Right? So, it's not just necessarily think every energetic status, 00:12:03.794 --> 00:12:07.994 but it's really about the integrity of the organism itself. 00:12:08.354 --> 00:12:11.854 And as soon as that control loop starts to become perturbed, 00:12:11.974 --> 00:12:14.354 that's when we start to see inflammatory responses. 00:12:14.854 --> 00:12:17.994 Right. Would that be reasonable? Do we link it to autopriasis in that sense? 00:12:18.254 --> 00:12:21.894 Yeah. I think one interesting application of that would be to help define thresholds. 00:12:21.894 --> 00:12:25.234 So like for particular pathways. 00:12:26.507 --> 00:12:31.287 Defining which ones perhaps are the, the original ones or the closest to the 00:12:31.287 --> 00:12:34.507 original ones, what were the original actual functions and seeing whether those 00:12:34.507 --> 00:12:37.907 functions are recapitulated at higher orders of org of organization. 00:12:38.207 --> 00:12:41.167 That I think would be very good. I think being able to, as you said, 00:12:41.287 --> 00:12:44.887 help help define what are the actual, uh, 00:12:45.087 --> 00:12:51.607 what are the actual interactions that, that cross a threshold from being normal 00:12:51.607 --> 00:12:54.867 everyday housekeeping to being something that's now quote inflammatory. 00:12:54.867 --> 00:12:57.967 Inflammatory um i think that would be quite quite 00:12:57.967 --> 00:13:00.927 useful it is very interesting that you talk about metabolism because 00:13:00.927 --> 00:13:05.267 now of course we're appreciating that metabolism and 00:13:05.267 --> 00:13:08.967 inflammation and immunity are highly linked so t-cell functions 00:13:08.967 --> 00:13:11.687 macrophage functions other inflammatory type cell 00:13:11.687 --> 00:13:15.327 functions are very dependent on metabolic 00:13:15.327 --> 00:13:18.607 fluxes and of course end up regulating metabolism right 00:13:18.607 --> 00:13:23.667 so but now if we go from single cell to multi-cell let's say we go to a slime 00:13:23.667 --> 00:13:31.527 mold or something simple would you see that when a slime mold um does it is 00:13:31.527 --> 00:13:36.027 the response of this collection of cells and make a slime mold already qualitatively 00:13:36.027 --> 00:13:37.887 different in case of inflammation. 00:13:38.567 --> 00:13:42.707 Than the single cylinder organism does 00:13:42.707 --> 00:13:45.627 a slime mold start to do different things i i 00:13:45.627 --> 00:13:49.027 think the slime mold starts to do different things because now there's 00:13:49.027 --> 00:13:52.027 an entire additional set of functions that come 00:13:52.027 --> 00:13:55.587 along that need to be optimized as 00:13:55.587 --> 00:13:59.187 as as a as a necessary uh uh 00:13:59.187 --> 00:14:05.807 as a necessary function of that additional cellularity so the there's a cost 00:14:05.807 --> 00:14:10.707 to to to maintaining that additional cellularity there's a greater distance 00:14:10.707 --> 00:14:16.607 uh there's a greater uh there's a greater need to have nuanced timescales of response, 00:14:16.987 --> 00:14:24.727 and now one might imagine that there's additional, of course, 00:14:24.727 --> 00:14:26.367 biological pathways that come 00:14:26.367 --> 00:14:30.527 along with doing that, and so then that system has to be synchronized. 00:14:30.627 --> 00:14:35.827 But yet, if one identifies what one might imagine are the core, 00:14:35.867 --> 00:14:39.327 core functions, those functions still have to be retained, right? 00:14:39.407 --> 00:14:42.907 So now how do you propagate from the single cell to the multi-cell while still 00:14:42.907 --> 00:14:45.707 retaining the overall qualitative behavior, right? 00:14:45.847 --> 00:14:49.867 That I think is where the really interesting insights will probably come along 00:14:49.867 --> 00:14:53.327 because that might actually even speak to. 00:14:55.197 --> 00:15:02.377 How each step of evolution necessitated an additional set of new branches that 00:15:02.377 --> 00:15:09.297 together had to be synchronized to achieve a macroscopic behavior of the entire system. Right. 00:15:10.097 --> 00:15:17.257 Yeah. So if you go now to the multicellular organism, would you see the reaction? 00:15:17.357 --> 00:15:22.217 So for instance, temperature change is a typical expression of an inflammation, right? 00:15:22.377 --> 00:15:26.897 Yes. Is temperature change also something that the single-cell organism would 00:15:26.897 --> 00:15:29.517 display or that the multi-cell organism will display? 00:15:30.237 --> 00:15:33.297 No, I mean, they're going to be dependent on their external environment, 00:15:33.497 --> 00:15:40.797 but they may very well respond differently than they do in terms of the temperature. 00:15:40.997 --> 00:15:48.257 So this whole heat shock response is intimately intertwined with inflammation. 00:15:48.257 --> 00:15:55.217 So heat shock proteins are actually a prototypical category of these damage 00:15:55.217 --> 00:15:58.497 associated molecular pattern molecules or damps as we call them. 00:15:58.497 --> 00:16:06.297 So they are molecules that do various housekeeping functions in their normal context, 00:16:06.497 --> 00:16:11.957 but when present in abnormal context, either in the wrong place or at the wrong 00:16:11.957 --> 00:16:15.577 time or in the wrong context of additional molecules, 00:16:15.857 --> 00:16:20.637 now become sensed as danger or alarm. 00:16:20.637 --> 00:16:27.537 And so, again, another interlinking between the environment, 00:16:27.697 --> 00:16:31.017 sensation of the environment, and adaptation to the environment, 00:16:31.137 --> 00:16:32.817 and inflammation, right? 00:16:32.857 --> 00:16:41.297 So, again, comes back to this thesis or hypothesis that inflammation is communication. 00:16:41.297 --> 00:16:45.957 Communication because at the end of the day, inflammation isn't, 00:16:45.957 --> 00:16:49.437 at some level, inflammation isn't a thing in and of itself normally. 00:16:49.797 --> 00:16:54.077 It's just a way of transmitting the information from a beginning to the end. 00:16:54.157 --> 00:17:00.017 It's just that when it rises above a certain threshold, because it's now intertwined 00:17:00.017 --> 00:17:03.057 with so many other pathways, inflammation now becomes. 00:17:04.956 --> 00:17:07.976 The causative agent or inflammation acquires the 00:17:07.976 --> 00:17:11.436 word inflammation becomes the word inflammation yes information information 00:17:11.436 --> 00:17:14.096 is information yeah you could say 00:17:14.096 --> 00:17:16.896 it's information or you could say it's communication it's sort of similar 00:17:16.896 --> 00:17:21.736 to non-specific because in some sense anything is information if you want right 00:17:21.736 --> 00:17:26.776 right so but not every single thing that's information can can become causative 00:17:26.776 --> 00:17:33.136 for something that that is pathological so yeah but if if if we if we would 00:17:33.136 --> 00:17:36.496 agree with this early definition of autopoiesis, 00:17:36.596 --> 00:17:39.196 self-maintenance of the organism as a system. 00:17:40.816 --> 00:17:44.896 This would require forms of communication between constituent components. 00:17:45.376 --> 00:17:53.476 But in the end, isn't it more a form of actuation to set in motion certain reactions 00:17:53.476 --> 00:17:56.756 at the lowest level, certain biochemical processes, 00:17:57.196 --> 00:18:01.676 to assure maintenance of the system? 00:18:01.676 --> 00:18:07.136 Yes. No, I would imagine that in a lower organism, it's perhaps more actuation 00:18:07.136 --> 00:18:10.196 because you're already a single cell. 00:18:10.316 --> 00:18:14.156 And so you don't really need to communicate. Although perhaps you communicate 00:18:14.156 --> 00:18:18.976 quorum sensing or, you know, in a sense you're communicating to nearby cells, that's possible. 00:18:19.676 --> 00:18:26.896 Communicating a sense that, you know, use your flagella to swim away from this 00:18:26.896 --> 00:18:28.676 and towards that or whatever. 00:18:28.676 --> 00:18:31.556 Ever uh but but yes i think at 00:18:31.556 --> 00:18:34.456 some very basic level it is actuation and then 00:18:34.456 --> 00:18:37.936 you could imagine that as you move up with evolutionary scale that actuation 00:18:37.936 --> 00:18:43.656 becomes subsumed into a set of biochemical pathways where they don't directly 00:18:43.656 --> 00:18:50.016 uh create motor uh actions in any given direction or another but actually transmit 00:18:50.016 --> 00:18:54.276 biochemically the sense that something must be done. 00:18:55.413 --> 00:18:58.933 Yes. So if you say transmitting that something must be done is actuation, 00:18:59.173 --> 00:19:01.913 then I'm perfectly okay with the word actuation. 00:19:02.093 --> 00:19:05.193 This is cool, right? Because now we have a media foundation to look at these 00:19:05.193 --> 00:19:10.593 more complex forms of inflammatory responses that you might find in those organ 00:19:10.593 --> 00:19:12.893 systems and so on, right? Right. So. 00:19:15.013 --> 00:19:19.473 And now you indicated, so because you also want to look really a little bit 00:19:19.473 --> 00:19:24.713 at how, okay, how does this possibly relate to the neural control of inflammatory response? 00:19:25.073 --> 00:19:31.333 And of course, brains start to emerge when, when you have to coordinate across 00:19:31.333 --> 00:19:34.593 multiple parts of, of a system, right. 00:19:34.633 --> 00:19:40.093 That cannot necessarily at a direct signaling level, level exchange information 00:19:40.093 --> 00:19:44.453 because they would not have the signal capacity. 00:19:44.733 --> 00:19:47.753 Right, it's too far apart, right, exactly, yes, yes. 00:19:47.973 --> 00:19:51.653 Or there might be transduction delays that you have to overcome and so on, right? 00:19:51.713 --> 00:19:56.993 So the brain starts to get involved as soon as you have a multi-component system, 00:19:57.333 --> 00:20:03.073 multi-organ system if you want, where you have to coordinate across these systems. 00:20:03.073 --> 00:20:08.893 So, that would suggest that if we talk about the skeletal muscle system, 00:20:09.073 --> 00:20:14.133 or you talk about, or use the muscle system to control if you're a worm, 00:20:14.273 --> 00:20:21.233 or we talk about regulation across the inflammatory responses of subsystems, right? Right. 00:20:21.453 --> 00:20:27.233 So how do you look at that? Do you see it like every subsystem has its own intrinsic 00:20:27.233 --> 00:20:31.073 inflammatory response or there's a perturbation, there will be an automatic reaction, 00:20:31.413 --> 00:20:37.933 predefined, genetically tightly controlled, that then has to be regulated yet 00:20:37.933 --> 00:20:41.933 again by either an immune system or a nervous system, right? 00:20:41.953 --> 00:20:44.393 So how do you see that these three components work together? 00:20:44.393 --> 00:20:48.693 So I think that it's actually sort of both. 00:20:48.893 --> 00:20:50.333 So you have... 00:20:52.569 --> 00:20:56.669 You have the organs, the typical, the typical organ structure, 00:20:56.849 --> 00:21:01.169 let's call it, let's say even at some level of tissue is, 00:21:01.409 --> 00:21:07.589 is the structural or functional cells or parenchymal cells that do the job that 00:21:07.589 --> 00:21:11.689 differentiates this organ from being this other organ, or this tissue from being this other tissue. 00:21:12.229 --> 00:21:16.749 Typically interspersed among them are these resident inflammatory cells like 00:21:16.749 --> 00:21:17.929 macrophages and others. 00:21:18.249 --> 00:21:21.269 And then typically touching on them are nerve termini. 00:21:21.529 --> 00:21:28.749 And so we can observe that the tissue in some sort of isolation will exhibit 00:21:28.749 --> 00:21:34.669 this inflammatory response, but we also exhibit coordination across tissues 00:21:34.669 --> 00:21:36.109 or across organs, right? 00:21:36.269 --> 00:21:43.469 And so for example, in some fields, people talk about the gut as the motor of inflammation, right? 00:21:43.489 --> 00:21:47.149 And of course, the gut has got its own innervation. It has a sort of primitive brain. 00:21:48.329 --> 00:21:53.229 The gut is quite central for many reasons in coordinating responses, 00:21:53.529 --> 00:21:56.089 but the brain is controlling the gut, right? 00:21:56.169 --> 00:21:58.669 So the gut can do its own inflammation. 00:21:59.669 --> 00:22:03.489 The liver can do its own inflammation. A lung can do its own inflammation, 00:22:03.689 --> 00:22:05.569 which makes sense, especially the lung, for example. 00:22:05.709 --> 00:22:08.829 You're breathing in particulates, though some of those may also be pathogens 00:22:08.829 --> 00:22:09.849 that you're breathing in. 00:22:09.909 --> 00:22:12.909 You have to to be able to deal with them locally and presumably 00:22:12.909 --> 00:22:16.049 you have to send information that you're dealing with them locally to the 00:22:16.049 --> 00:22:20.369 brain and then the brain kind of keeps tabs on this and and says okay are you 00:22:20.369 --> 00:22:23.929 is is the branch office doing a good enough job of dealing with this or do we 00:22:23.929 --> 00:22:28.169 need to involve the head office but it's not that you wait necessarily i would 00:22:28.169 --> 00:22:32.169 think until the problem is out of hand at the branch office you're you're sort 00:22:32.169 --> 00:22:34.349 of keeping tabs right then at some point. 00:22:36.249 --> 00:22:39.109 That is also the the act of 00:22:39.109 --> 00:22:43.129 keeping tabs at the brain level presumably is also 00:22:43.129 --> 00:22:48.009 activating pathways in other organs for whatever appropriate reason either for 00:22:48.009 --> 00:22:53.409 a need to further ramp up or because for example a pathogen can can can evolutionarily 00:22:53.409 --> 00:22:57.089 have been anticipated to move from one organ to another through the blood or 00:22:57.089 --> 00:23:01.729 through the nervous system right so the threat is this dynamic is is evolving dynamically. 00:23:02.069 --> 00:23:06.829 And so then the system is kind of doing its best guess at how to evolve dynamically, right? 00:23:06.889 --> 00:23:12.089 And as long as it's all under control, the threat or the damage is dealt with 00:23:12.089 --> 00:23:13.489 in some fashion, it's contained. 00:23:13.629 --> 00:23:19.249 And then there's an element of having already from the beginning started some 00:23:19.249 --> 00:23:21.969 anti-inflammatory, meaning stopping functions. 00:23:22.049 --> 00:23:26.609 And also these same functions are pro-healing. And so you're beginning the healing cascade as you go. 00:23:26.689 --> 00:23:29.829 If it all works out great, uh everybody at the 00:23:29.829 --> 00:23:32.869 brain level kind of uh congratulates themselves that 00:23:32.869 --> 00:23:38.049 the the crisis was main was was addressed um and then some amount of time later 00:23:38.049 --> 00:23:42.809 the tissues return to some sort of homeostatic uh state that's compatible with 00:23:42.809 --> 00:23:48.089 life as a as a as a system but the problem becomes i think when either the thread 00:23:48.089 --> 00:23:51.029 is too large the it moves too fast um. 00:23:52.452 --> 00:23:57.912 Persists for too long, or because of the other evolutionary trade-off, 00:23:57.932 --> 00:23:59.912 which is genetic variability that we have to have. 00:24:00.012 --> 00:24:06.592 You have a particular organism whose genetic variability makes him or her that 00:24:06.592 --> 00:24:09.512 much more prone to respond. 00:24:10.612 --> 00:24:15.412 I think more prone to respond to assess damage and think I have too much damage 00:24:15.412 --> 00:24:19.052 or more damage than I actually have, or I have more stress than I actually have. 00:24:19.232 --> 00:24:22.952 That's often tied to pain, right? Pain is very subjective. 00:24:24.032 --> 00:24:27.652 There isn't any clear molecular correlate of pain. It's something that you have 00:24:27.652 --> 00:24:28.812 to kind of assess subjectively. 00:24:28.872 --> 00:24:32.252 And coincidentally, of course, that is a very much a nervous system phenomenon. 00:24:32.452 --> 00:24:38.112 So it's very possible that an organism is at a genetic level, 00:24:38.212 --> 00:24:41.532 somewhat overly sensitive or potentially the other way around, 00:24:41.572 --> 00:24:42.932 not sensitive enough, right? 00:24:43.012 --> 00:24:45.492 But you need that range in the population to just evolve. 00:24:47.872 --> 00:24:51.192 So which means that that individual will now become sick. 00:24:51.352 --> 00:24:57.172 That inflammatory response will progress further than it ought to. 00:24:57.692 --> 00:25:00.832 And now that can lead to all kinds of detrimental consequences. 00:25:01.192 --> 00:25:04.012 You would imagine at the farthest end, evolutionarily speaking, 00:25:04.252 --> 00:25:06.932 that if it's incompatible with life, the damage is too much, 00:25:07.012 --> 00:25:11.552 this organism dies, those genes presumably are not passed on, 00:25:12.212 --> 00:25:13.572 an editing process has occurred. 00:25:13.792 --> 00:25:15.952 So inflammation even subserves that role. 00:25:17.372 --> 00:25:20.892 We moved a bit fast now. So if you take the example of the lung, right? 00:25:20.952 --> 00:25:23.652 So okay, I have particulate matter and then there's the lung, 00:25:23.832 --> 00:25:27.092 it triggers an inflammatory response. 00:25:27.832 --> 00:25:30.932 Now, who wants to know about that for what reason, right? 00:25:31.032 --> 00:25:37.132 If we take this sort of more anthropomorphic perspective, before even the brain 00:25:37.132 --> 00:25:41.592 starts to worry about this, which other organ would even care, right? 00:25:41.632 --> 00:25:46.112 The heart might care because, okay, lung capacity is going down. So I got to pump harder. 00:25:46.292 --> 00:25:48.772 So I want to know about this as an example. Yes. 00:25:49.492 --> 00:25:53.392 So, so in that sense, in terms of, if we take, get this, this, 00:25:53.512 --> 00:25:56.032 this, this perspective of maintaining the integrity of the organism. 00:25:57.548 --> 00:26:02.128 Who wants to know about any kind of perturbations at the level of the lung? 00:26:02.728 --> 00:26:06.408 Well, at some level, if you're in an environment where you're breathing in toxic 00:26:06.408 --> 00:26:10.368 materials, you might need to actuate functions that, you know, 00:26:10.368 --> 00:26:14.288 that activate a program to move you away from that environment, right? 00:26:14.428 --> 00:26:16.968 A kind of survival program. This is a noxious environment. 00:26:17.148 --> 00:26:20.328 I need to move. Those functions are already there, right? At some level, 00:26:20.348 --> 00:26:21.388 the brain is already doing that. 00:26:21.948 --> 00:26:26.648 But maybe that's not for such a rapid and massive change that says, 00:26:26.808 --> 00:26:30.688 you know, I'm I'm living in, all of a sudden I've been put into a very low oxygen 00:26:30.688 --> 00:26:33.688 or a very high CO2 environment and I need to propel myself out of there. 00:26:33.868 --> 00:26:37.808 I may be in something that's a more slowly evolving threat on that timescale. 00:26:38.148 --> 00:26:42.928 I'm only finding out about it three hours later, right? And so then maybe that 00:26:42.928 --> 00:26:48.128 triggers a sensation that you need to get out of there and go somewhere else. 00:26:48.308 --> 00:26:51.048 But yeah, of course, other organs in the meantime are also going 00:26:51.048 --> 00:26:54.928 to need to be responding to adjust their physiology appropriately to this new 00:26:54.928 --> 00:26:59.208 load you you cannot do what you were doing before because you're also dealing 00:26:59.208 --> 00:27:04.188 with this additional uh particular or pathogenic burden or some other type of 00:27:04.188 --> 00:27:09.328 damage i now need to compensate around that uh a key one one one obvious one is in. 00:27:10.068 --> 00:27:16.708 Following injury you will have you may have severe bleeding um a key inflammatory 00:27:16.708 --> 00:27:20.988 mediator interleukin-6 activates the coagulation cascade. 00:27:21.268 --> 00:27:27.368 So you're rapidly activating a coagulation cascade to close up that hole. 00:27:27.828 --> 00:27:29.728 Of course, the problem is that 00:27:29.728 --> 00:27:33.248 the coagulation cascade now feeds back and activates more inflammation. 00:27:33.548 --> 00:27:38.388 Because, I don't know if because, but at least you can speculate that if you 00:27:38.388 --> 00:27:41.128 have a big hole in your body, the next thing that's coming is a massive wave 00:27:41.128 --> 00:27:43.968 of bacteria from your own skin or from the environment or whatever. 00:27:44.128 --> 00:27:48.828 So there's going to be an invasive an invasive pathogenic opportunity there from that hole, right? 00:27:48.908 --> 00:27:53.088 It's not that the body is sensing the hole necessarily, but it's sensing that 00:27:53.088 --> 00:27:56.908 there's a blood loss, which must be due to a hole, right? 00:27:56.968 --> 00:28:02.988 So now you're activating a pathway of coagulation, and perhaps it's disseminated, 00:28:03.008 --> 00:28:04.288 which happens in multiple places. 00:28:05.758 --> 00:28:10.018 Perhaps because, again, it's preemptively coagulating because bacteria will 00:28:10.018 --> 00:28:12.518 probably be entering and so they'll get to various places. 00:28:12.638 --> 00:28:16.618 And so now you need to coagulate to create barriers to trap these bacteria. 00:28:16.778 --> 00:28:22.258 That coagulation is pro-inflammatory, again, because you need to wind yourself 00:28:22.258 --> 00:28:27.038 up for the eventuality that you might have a pathogenic fight on top of your 00:28:27.038 --> 00:28:28.498 traumatic injury fight. 00:28:29.398 --> 00:28:33.098 If all of that gets spun up too much out of control because there's an inherent, 00:28:33.098 --> 00:28:37.998 very strong positive feedback, you could imagine in a setting that's not supported 00:28:37.998 --> 00:28:41.418 by modern medicine, that's now no longer compatible with life. 00:28:41.558 --> 00:28:45.678 And so then the organism will die. And even that's good because the organism's 00:28:45.678 --> 00:28:51.398 death means that that organism is not transmitting the pathogenic agent to the rest of the population. 00:28:51.438 --> 00:28:54.918 And if it's a trauma and not with a pathogenic population. 00:28:55.238 --> 00:28:59.958 Well, that organism is not bringing the predator back to the rest of the population, 00:28:59.958 --> 00:29:03.258 right so even at an evolutionary level 00:29:03.258 --> 00:29:07.098 you could imagine that this is actually something that's that's beneficial 00:29:07.098 --> 00:29:10.598 evolutionary but it means for these multi-organ uh systems 00:29:10.598 --> 00:29:13.678 there are predefined response patterns 00:29:13.678 --> 00:29:16.338 as you now describe them yes so how big is that 00:29:16.338 --> 00:29:20.898 repertoire you think so you're talking about the that that the organ specific 00:29:20.898 --> 00:29:24.998 response pattern so yeah we we've we've addressed address some of that by trying 00:29:24.998 --> 00:29:31.178 to look at a defined panel of inflammatory mediators that interrogates a broad 00:29:31.178 --> 00:29:35.758 array of inflammatory and immune pathways that are known to sort of be interlinked. 00:29:35.798 --> 00:29:40.758 And when you do that, and you do that in response to a sort of a prototypical stimulus, 00:29:40.838 --> 00:29:46.898 which is sort of one molecule derived from bacteria that is a known potent amino stimulant, 00:29:46.918 --> 00:29:49.918 so you're using that as a sort of prototypical system that you 00:29:49.918 --> 00:29:52.878 can control and you can uh you can 00:29:52.878 --> 00:29:56.038 actuate quantitatively um you do 00:29:56.038 --> 00:29:59.258 find uh quite different dynamic 00:29:59.258 --> 00:30:03.138 responses in an organ specific fashion um you 00:30:03.138 --> 00:30:08.778 can kind of on depending on the tools you use you can uh quantify peaks and 00:30:08.778 --> 00:30:13.678 valleys in this dynamic process and begin to think that you that there is a 00:30:13.678 --> 00:30:20.878 sort of programmed temporal wave or spatio-temporal wave of this inflammatory response. 00:30:21.558 --> 00:30:24.638 And that it is 00:30:24.638 --> 00:30:27.598 presumably happening that way 00:30:27.598 --> 00:30:31.458 for some evolutionarily conserved 00:30:31.458 --> 00:30:34.658 reason that relates to the 00:30:34.658 --> 00:30:37.478 likelihood that that specific pathogen is what you've 00:30:37.478 --> 00:30:40.358 got and the pathways by 00:30:40.358 --> 00:30:44.278 which that pathogen may disseminate or the locations to which that pathogen 00:30:44.278 --> 00:30:49.778 may go and cause very serious harm versus not so serious harm are those ones 00:30:49.778 --> 00:30:53.878 that are responding sooner versus later and so forth of course those are all 00:30:53.878 --> 00:30:59.218 hypotheses to be tested at something but the way you describe it now sounds like um. 00:31:00.546 --> 00:31:03.986 A large chunk of of the inflammatory response 00:31:03.986 --> 00:31:06.786 is relying on these 00:31:06.786 --> 00:31:10.406 predefined response patterns at the organ level i 00:31:10.406 --> 00:31:15.626 i think so i mean because because it at some level the organ is a compendium 00:31:15.626 --> 00:31:19.746 of its cells right even if we took out the potential for neural control now 00:31:19.746 --> 00:31:23.026 okay because the alternative hypo or the related not necessarily alternative 00:31:23.026 --> 00:31:27.866 hypothesis is that the reason or that we see these organ-specific patterns is 00:31:27.866 --> 00:31:29.946 because of the way neural control works. 00:31:30.046 --> 00:31:34.966 Which regions of the brain activate first, second, third, and where do they 00:31:34.966 --> 00:31:37.446 project, and where does that response happen? 00:31:37.606 --> 00:31:40.566 At some level, I think it's a semantic argument. My guess is evolution would 00:31:40.566 --> 00:31:45.206 not have gone that way if it wasn't beneficial to activate inflammation in a 00:31:45.206 --> 00:31:48.386 particular sequence, I would guess. 00:31:48.566 --> 00:31:53.566 But at some level, an organ is a compendium of the cells that it has. 00:31:53.746 --> 00:31:58.466 Some organs have a a greater proportion of sort of their parenchymal cells relative 00:31:58.466 --> 00:32:02.546 to their resident inflammatory cells than other organs. 00:32:03.346 --> 00:32:05.986 A prototypical organ is, again, the intestine, the gut. 00:32:06.886 --> 00:32:11.186 Of course, we all know the gut is really the outside of the body at some level, 00:32:11.286 --> 00:32:13.566 right? So you, of course, in the lung is another one. 00:32:13.646 --> 00:32:17.966 So these are surfaces that are directly, essentially in contact with the outside world. 00:32:18.266 --> 00:32:23.666 It's not illogical to assume that these are ones that need to be very finely 00:32:23.666 --> 00:32:27.646 tuned in terms of how they regulate their inflammatory response because you 00:32:27.646 --> 00:32:30.586 are constantly impacted by the outside world, 00:32:30.766 --> 00:32:34.646 you can't have a situation where you're constantly inflaming out of control 00:32:34.646 --> 00:32:40.246 and having all of your organs kick in for any stimulus that comes along. 00:32:40.686 --> 00:32:47.986 There have to be very high thresholds that have to be exceeded in order to really 00:32:47.986 --> 00:32:50.366 get the cascade flowing downstream. 00:32:50.706 --> 00:32:55.266 There's other organs that are obviously more internal that if they come into 00:32:55.266 --> 00:32:58.646 contact with a bacterial-derived immunostimulant molecule. 00:33:00.348 --> 00:33:04.648 The interpretation must be there's bacteria already inside, right? 00:33:04.748 --> 00:33:07.288 They're already present. They already have made it through the barriers. 00:33:07.748 --> 00:33:12.168 So activate right away, right? You could imagine that that would be the program. 00:33:12.328 --> 00:33:16.908 And there's some seminal papers about gut inflammation, the ones that define 00:33:16.908 --> 00:33:22.928 some of the prototypical actions and regulation of the key signaling pathways 00:33:22.928 --> 00:33:27.388 for inflammation like NF-kappa B that show that the gut is sort of wired like that. 00:33:27.388 --> 00:33:32.168 It's pretty much stepping on the brake pedal until a fairly high threshold is 00:33:32.168 --> 00:33:36.228 exceeded, and then the foot is lifted off the brake pedal, and that creates motion. 00:33:36.508 --> 00:33:37.948 Now there's a response. 00:33:38.768 --> 00:33:42.348 Other organs have got the foot much more lightly on the brake pedal. 00:33:42.868 --> 00:33:47.088 Now what you call the inflammatory response, if I compare the inflammatory response 00:33:47.088 --> 00:33:51.448 in the lung, how is that different from the inflammatory response in the liver 00:33:51.448 --> 00:33:54.228 or the spleen or the heart? 00:33:55.248 --> 00:34:03.268 I mean, the molecules that evolve, they might evolve at different times depending 00:34:03.268 --> 00:34:05.988 on thresholds, but they're often very similar. 00:34:06.068 --> 00:34:10.448 There are some molecules that are more present in certain tissues than others. 00:34:10.448 --> 00:34:13.468 Um often when people say inflammatory 00:34:13.468 --> 00:34:16.168 response they sort of are mixing the terms and and are 00:34:16.168 --> 00:34:19.188 talking about not just with inflammation and meaning the 00:34:19.188 --> 00:34:22.268 the direct molecular actions being driven by 00:34:22.268 --> 00:34:26.288 the direct molecules that we can say are inflammatory but then sort of the secondary 00:34:26.288 --> 00:34:30.568 phenomena so for example edema you know so in the lung you will have lung edema 00:34:30.568 --> 00:34:34.968 you might not have it quite as much in say the liver or something like that 00:34:34.968 --> 00:34:41.148 um so or the gut right so it just depends on the, on the, on the, the, 00:34:41.308 --> 00:34:45.768 the, the secondary function that, that, or dysfunction that becomes triggered 00:34:45.768 --> 00:34:48.228 is often also very organ specific. 00:34:48.388 --> 00:34:53.408 But I think that the, the actual mediators that one finds are often a fairly 00:34:53.408 --> 00:34:56.368 well-ordered cascade of, of, of mediators. 00:34:56.508 --> 00:35:01.828 Um, they're typically the earliest responses, let's say to a tissue injury in 00:35:01.828 --> 00:35:03.948 that particular organ are going to be these damps, 00:35:04.760 --> 00:35:07.520 After that is a class of these cytokines that we call chemokines. 00:35:07.620 --> 00:35:13.660 They typically are there to help attract circulating inflammatory cells to the 00:35:13.660 --> 00:35:15.540 local area, but they actually have many other functions. 00:35:16.800 --> 00:35:19.820 And then the classical cytokines, right? 00:35:19.860 --> 00:35:22.900 The problem is it's not like the first thing, then you wait a while, 00:35:22.940 --> 00:35:24.840 then the second thing, and then you wait a while, and the third thing. 00:35:24.920 --> 00:35:26.600 These networks organize very fast. 00:35:26.940 --> 00:35:32.080 And then the next behavior that is very interesting is that they organize very fast across multiple 00:35:32.240 --> 00:35:34.880 tissues where you begin to think that 00:35:34.880 --> 00:35:37.900 the only way that could happen is if there was neural control right because 00:35:37.900 --> 00:35:40.700 how else do you how else can you explain a situation 00:35:40.700 --> 00:35:45.460 where a leg is broken severely and already the gut is beginning to have a problem 00:35:45.460 --> 00:35:49.020 right it's beginning to change its inflammatory profile and then let's say the 00:35:49.020 --> 00:35:54.400 liver and then the lung uh these distal responses that are sensed almost immediately 00:35:54.400 --> 00:35:58.340 right that cannot happen just through simple diffusion Yeah. 00:35:58.540 --> 00:36:04.380 So you introduced this model by Namas and others where they actually distinguished 00:36:04.380 --> 00:36:08.800 sort of three profiles of the inflammatory response, right? 00:36:08.840 --> 00:36:11.520 Where you were talking about, let's say, an etiquette response where you remain 00:36:11.520 --> 00:36:16.840 within the range, which is still supporting the integrity of the organism, 00:36:16.980 --> 00:36:21.400 but there you were making the point it never returns to the baseline. You always change. 00:36:21.740 --> 00:36:25.220 Yes. So you're always not just change, you're typically worse off. 00:36:25.220 --> 00:36:29.640 So, you're leaving behind traces of inflammation. 00:36:29.920 --> 00:36:32.980 You're not simply completely resolving and coming down to baseline. 00:36:33.420 --> 00:36:36.860 So, the additive is also... And which means that the next time that you get 00:36:36.860 --> 00:36:41.180 hit with a stimulus, you're already being hit not at a baseline of zero, 00:36:41.320 --> 00:36:42.660 but at a baseline of plus one. 00:36:43.100 --> 00:36:48.100 And that is why preconditioning, studying preconditioning, and mathematically 00:36:48.100 --> 00:36:51.220 modeling preconditioning have been activities that we've been very interested 00:36:51.220 --> 00:36:54.320 in since the beginning of this process. because, of course, you're never naive. 00:36:54.380 --> 00:36:56.160 You've never been exposed to only one thing. 00:36:56.260 --> 00:36:59.140 By definition, you've already been exposed to a bunch of things by the time 00:36:59.140 --> 00:37:02.540 you're exposed to whatever it is that you're studying, whether experimentally or clinically. 00:37:02.780 --> 00:37:04.860 So to those who mean from a clinical perspective... 00:37:06.578 --> 00:37:11.418 The inflammatory response of every individual patient is uniquely different 00:37:11.418 --> 00:37:13.838 because they are at a different set point. Exactly. 00:37:14.158 --> 00:37:18.298 It's all the prototypical complex system. Initial conditions are perhaps the 00:37:18.298 --> 00:37:19.118 biggest single determinant. 00:37:19.518 --> 00:37:24.618 Okay. And then you also mentioned that the DART can have an excessive response 00:37:24.618 --> 00:37:26.818 that exceeds some threshold, right? 00:37:26.858 --> 00:37:34.598 Or you can have, let's say, a hypoinflammatory response that is sort of more reduced than expected. 00:37:34.878 --> 00:37:38.398 Right. And in both cases, you're outside of this envelope that would sustain 00:37:38.398 --> 00:37:41.438 the organism, right? So why is that significant? 00:37:41.738 --> 00:37:45.078 So in both instances, things should be really strongly supported by empirical evidence? 00:37:45.478 --> 00:37:57.278 Yeah, so we have in one sort of clinical system where we think we can get, 00:37:57.418 --> 00:37:59.158 where we've made many of these insights, 00:37:59.338 --> 00:38:01.958 which is severe traumatic injury. 00:38:01.958 --> 00:38:05.038 In a large population study observational 00:38:05.038 --> 00:38:08.078 study where you know in approximately 500 patients where 00:38:08.078 --> 00:38:10.818 we could first of all interrogate a broad 00:38:10.818 --> 00:38:14.038 array of injury severity so it wasn't just focusing on the most severely injured 00:38:14.038 --> 00:38:17.778 patient it was really a survey across injury severities which was very important 00:38:17.778 --> 00:38:22.098 because you could see the entire envelope of responses and over a pretty long 00:38:22.098 --> 00:38:28.358 period of time we could find sub cohorts of these patients that exhibit these 00:38:28.358 --> 00:38:29.558 phenomena now i mean I mean, 00:38:29.558 --> 00:38:33.678 the original picture that you described was a hypothesis. 00:38:35.758 --> 00:38:41.918 It was, yeah, it was derived from, let's say, clinical experience and maybe 00:38:41.918 --> 00:38:45.538 experimental experience where there's a sense that this is what happens. 00:38:45.658 --> 00:38:51.018 But with being able to actually measure the mediators, create dynamic network 00:38:51.018 --> 00:38:57.898 representations of those mediators, we can, in fact, point to cohorts of patients 00:38:57.898 --> 00:38:59.938 and circumstances under which we see each piece. 00:39:00.078 --> 00:39:04.998 So for example, if you compare highly matched patients that went on to live 00:39:04.998 --> 00:39:06.358 versus went on to die, sort of 00:39:06.358 --> 00:39:09.698 the biggest bifurcation you can have in anything, but of course in trauma, 00:39:09.838 --> 00:39:16.438 you can see the sense of self-sustaining inflammation with networks, 00:39:16.898 --> 00:39:20.078 complexity that rises and rises from pretty much as soon as you can, 00:39:20.118 --> 00:39:24.738 excuse me, as soon as you can measure versus other networks that look sort of 00:39:24.738 --> 00:39:26.758 flatlined and just not responsive at all. 00:39:27.278 --> 00:39:32.738 That's one case. We have patients that have a phenotype of coagulopathy, 00:39:32.798 --> 00:39:36.618 so they're just not coagulating appropriately, or then later on they're over-coagulating. 00:39:36.738 --> 00:39:41.318 And when you look at them, they also, compared to highly matched controls that 00:39:41.318 --> 00:39:47.038 don't have that phenomenon, look like they have just an insufficient inflammatory response. 00:39:47.298 --> 00:39:50.658 And then if you, again, to bring it back to the brain, when we compare. 00:39:52.175 --> 00:39:58.895 The networks of patients that have a spinal cord injury versus highly matched 00:39:58.895 --> 00:40:04.995 patients with similar injury characteristics, but that don't have that spinal cord injury, 00:40:05.155 --> 00:40:07.755 we now again see this hypoinflammation. 00:40:07.895 --> 00:40:15.695 So there's clearly situations that, whether they're all related to each other. 00:40:15.795 --> 00:40:21.015 I mean, for example, the one inference would be that if the spinal cord transection 00:40:21.015 --> 00:40:23.775 gives gives you this profound hypoinflammation. 00:40:24.095 --> 00:40:27.875 Is that relevant for anybody that doesn't have spinal cord transection? 00:40:28.115 --> 00:40:34.335 Does that, I mean, or does it mean that those patients have some degree of neural dysfunction, right? 00:40:34.435 --> 00:40:38.075 Our hypothesis is that we're looking at patients, when we see patients that 00:40:38.075 --> 00:40:41.135 have this hypoinflammation, that they have some degree of neural dysfunction. 00:40:42.075 --> 00:40:45.515 Now, what type of neural dysfunction, I don't know, but we can potentially suggest 00:40:45.515 --> 00:40:49.295 some biomarkers, inflammatory biomarkers that appear to be hallmarks of that. 00:40:50.295 --> 00:40:54.655 Likewise, in the case of But the overly revved up, overly stimulated, 00:40:54.755 --> 00:40:58.735 over-exuberant inflammatory response, again, we can have biomarkers that go 00:40:58.735 --> 00:41:00.075 along with that, and they're different. 00:41:00.935 --> 00:41:04.435 So, yeah, the suggestion is that different programs have been set in motion. 00:41:05.035 --> 00:41:10.295 And the hypothesis for the spinal cord lesion case is that as soon as you detect 00:41:10.295 --> 00:41:12.115 that the blood-brain barrier is compromised. 00:41:12.515 --> 00:41:17.195 You actually want to reduce the inflammatory response to prevent any from these 00:41:17.195 --> 00:41:20.195 signaling molecules actually enter the nervous system. 00:41:20.195 --> 00:41:22.835 Because that's a that's a terrific hypothesis that will be 00:41:22.835 --> 00:41:26.555 huge right because then information hits your nervous system and 00:41:26.555 --> 00:41:29.575 that might be the end of a lot of things so the whole concept 00:41:29.575 --> 00:41:36.355 of a kind of uh hibernation or stasis um that that is the as a as a protective 00:41:36.355 --> 00:41:42.995 mechanism um and i think is absolutely key and i think there's many links to 00:41:42.995 --> 00:41:49.175 inflammation being playing a big role in and communicating that and mediating that. Yeah, so I agree. 00:41:49.435 --> 00:41:56.175 That's a terrific idea. Okay, so now we have the sort of three ranges of responses 00:41:56.175 --> 00:42:00.015 to inflammation, which clearly points to this being a control issue. 00:42:00.115 --> 00:42:06.295 This is a controlled response, but the control can be sort of showing too much 00:42:06.295 --> 00:42:08.215 positive or negative feedback. That's right. 00:42:08.575 --> 00:42:11.355 And also you mentioned in your talk that you see this 00:42:11.355 --> 00:42:14.355 inflammatory response very much as an interaction between 00:42:14.355 --> 00:42:17.315 positive to her negative feedback loops yes i mean obviously that's 00:42:17.315 --> 00:42:20.395 a fairly straightforward way to look at any complex system 00:42:20.395 --> 00:42:24.535 uh but we've developed a set 00:42:24.535 --> 00:42:28.255 of sort of let's call them proto-interactions if 00:42:28.255 --> 00:42:30.955 you want to think about the the functions that might have been there at the 00:42:30.955 --> 00:42:37.135 earliest at the earliest stage of evolution that we can um that we can play 00:42:37.135 --> 00:42:41.375 forward we can we can encode them into mathematical models and we can reproduce 00:42:41.375 --> 00:42:46.095 a range of both qualitative and then quantitative behaviors. 00:42:46.695 --> 00:42:49.875 If we code that set of interactions with that key. 00:42:52.031 --> 00:42:55.051 That key tug of war between 00:42:55.051 --> 00:42:58.431 positive versus negative feedback into agent-based 00:42:58.431 --> 00:43:01.091 models that are say spatially realistic we can 00:43:01.091 --> 00:43:04.131 reproduce patterns that we see in real in real human 00:43:04.131 --> 00:43:11.331 microscopic sort of histology or even macroscopic lesions and so that doesn't 00:43:11.331 --> 00:43:15.751 automatically prove that we're right but we've been we've been able to make 00:43:15.751 --> 00:43:21.351 those leaps because we base them on that that core set of hypotheses of these specific. 00:43:22.691 --> 00:43:24.931 Positive versus negative feedbacks. Yes. 00:43:25.011 --> 00:43:28.551 But I think there are two really interesting consequences of that, 00:43:28.631 --> 00:43:31.751 right? Because you were saying, well, it's not just sequential. 00:43:31.931 --> 00:43:34.871 At first, I'm ramping something up, and then I'm ramping it down. 00:43:35.071 --> 00:43:38.871 Yes. It's very much that positive and negative feedback are operating in parallel. 00:43:39.071 --> 00:43:42.531 In parallel. That seems to be the case. I think this is rather an important 00:43:42.531 --> 00:43:46.471 insight, but the question would be, of course, what's the advantage of that? 00:43:46.591 --> 00:43:47.791 Why would you do it that way? 00:43:48.811 --> 00:43:55.971 Yeah, so it's been very interesting to think about why it is that such a system 00:43:55.971 --> 00:43:57.371 would have evolved that way. 00:43:57.511 --> 00:44:02.431 You could imagine that that's a way to give you much more fine-grained control, 00:44:02.491 --> 00:44:07.051 more rapid control, more nuanced control. 00:44:07.051 --> 00:44:14.431 I also think that at some level, the body or the organism has to sort of, 00:44:14.451 --> 00:44:18.711 its baseline state has to be somewhat anti-inflammatory because of the fact 00:44:18.711 --> 00:44:22.111 that so many perturbations will be pro-inflammatory. 00:44:22.111 --> 00:44:28.531 So the baseline state is not zero, but it's actually trending towards anti-inflammation. 00:44:28.631 --> 00:44:32.571 So for example, let's take something simple. 00:44:33.811 --> 00:44:38.531 Muscle stretching as a function of just daily activity, walking within a range, 00:44:38.671 --> 00:44:42.371 nothing severe, nothing athletic, nothing stress response, fight or flight. 00:44:42.511 --> 00:44:45.771 You're just walking, dealing with normal activity. 00:44:45.771 --> 00:44:49.031 We did some 00:44:49.031 --> 00:44:52.171 work in collaboration with with with other investigators that 00:44:52.171 --> 00:44:55.431 you can you can replicate that as cyclic stress and 00:44:55.431 --> 00:45:00.151 cyclic stretch in a in a cell culture system and what you're seeing is an elaboration 00:45:00.151 --> 00:45:04.831 a tonic elaboration of key uh sort of anti-inflammatory pro-healing mediators 00:45:04.831 --> 00:45:12.931 now simulate a much more dynamic process exercise uh uh sort of fight or flight need to run. 00:45:13.011 --> 00:45:16.671 Now you're stretching faster or bigger sort of amplitudes. 00:45:17.071 --> 00:45:22.331 That entire regime switches over to activation of pro-inflammatory pathways. So- 00:45:23.729 --> 00:45:29.089 So the point is that the system will never know when it needs to switch from 00:45:29.089 --> 00:45:34.009 being just doing its normal amount of movement, if you will, 00:45:34.129 --> 00:45:36.789 to the needing to instantly need to run. 00:45:36.909 --> 00:45:42.129 And you can't trade off evolutionarily. You can't be always inflamed on the 00:45:42.129 --> 00:45:44.289 off chance that you might need to become more inflamed. 00:45:44.569 --> 00:45:49.109 And so then you need to basically have this available bifurcation at almost 00:45:49.109 --> 00:45:53.809 every time step. And every time step, you need to be able to choose to go to 00:45:53.809 --> 00:45:56.329 the right or to the left, to go to pro or to go to anti. 00:45:56.409 --> 00:46:01.389 But not inflamed would mean at the level of the tissue, we need a zero expression 00:46:01.389 --> 00:46:06.029 of any of the markers of inflammation or just a low expression of these markers? 00:46:06.709 --> 00:46:13.089 I think that we get a tonic expression of key anti-inflammatory mediators. 00:46:13.429 --> 00:46:17.409 I think sometimes we can find what look 00:46:17.409 --> 00:46:21.429 like baseline levels of pro-inflammatory mediators but 00:46:21.429 --> 00:46:24.609 they often are there because they're also subsuming other 00:46:24.609 --> 00:46:27.849 physiologic functions or the experimental 00:46:27.849 --> 00:46:31.569 situation we cannot ever truly demonstrate 00:46:31.569 --> 00:46:34.449 that we didn't create some stress in the process of 00:46:34.449 --> 00:46:38.709 creating the experiment to look so there's always that kind of heisenberg uncertainty 00:46:38.709 --> 00:46:41.849 you know the fact that we're observing it is creating the situation that we're 00:46:41.849 --> 00:46:46.369 observing so but in terms of the negative feedback is a negative feedback an 00:46:46.369 --> 00:46:53.189 expression of anti-inflammatory mediators or a suppression of the inflammatory mediators or both. 00:46:53.389 --> 00:46:56.609 Yeah. So this is a big argument in the field right now. And I don't know if 00:46:56.609 --> 00:47:00.269 some of it is semantic or if it actually is a specific thing. 00:47:00.949 --> 00:47:04.769 People talk about resolution, inflammation resolution. You will see this word 00:47:04.769 --> 00:47:08.149 coming up in many papers. And these are very good, very respected investigators. 00:47:08.489 --> 00:47:15.109 There clearly are entire programs whose job it is to resolve inflammation after the fact. 00:47:15.109 --> 00:47:17.969 I think that those are related but 00:47:17.969 --> 00:47:20.689 distinct I think there are two levels there is the 00:47:20.689 --> 00:47:24.749 level of control and decision making some of 00:47:24.749 --> 00:47:27.589 which can stretch out to a longer period of time and then some 00:47:27.589 --> 00:47:31.569 of these same mediators can drive secondary functions that are pro-healing and 00:47:31.569 --> 00:47:35.149 then there's the actual longer term process so it's a well-known feature of 00:47:35.149 --> 00:47:40.529 wound healing that you can sort of shut off that initial inflammatory phase 00:47:40.529 --> 00:47:46.269 and you can even begin to heal a tissue over the next longer time scale, 00:47:46.309 --> 00:47:50.769 but to truly remodel all the way back to something like what you were before 00:47:50.769 --> 00:47:52.629 the injury takes a very long time. 00:47:52.709 --> 00:47:58.149 So you, you, but you were able to kind of, you know, put a bandaid on the problem 00:47:58.149 --> 00:48:01.649 and it just takes a while for the problem to fully, you know, 00:48:01.649 --> 00:48:07.409 at least achieve enough of a scar or whatever to, uh, to further shore up that repair. 00:48:07.609 --> 00:48:10.709 Um, there are many aspects of, 00:48:10.769 --> 00:48:14.849 of, of healing after injury that don't have that skin wound healing kind of 00:48:14.849 --> 00:48:19.309 vocabulary, but it's that same basic idea that you need to, you need to kind 00:48:19.309 --> 00:48:22.569 of shore up the, the, the, the, the, the, the, the, the, the, 00:48:22.569 --> 00:48:22.749 the, the, the, the, the, the. 00:48:23.351 --> 00:48:29.511 Broken or disturbed tissue so that it can go back to doing at least some aspect 00:48:29.511 --> 00:48:35.051 of its job and probably to turn off signaling that tells other organs that there's a problem. 00:48:35.211 --> 00:48:38.651 So you kind of quiet that whole thing down. And then once that's done, 00:48:38.791 --> 00:48:42.931 you can give some time for the resolution processes to really just do their job. 00:48:43.411 --> 00:48:46.571 I think that when you're looking at chronic inflammatory settings, 00:48:46.731 --> 00:48:52.051 which as I mentioned in my talk, I think is more like a chronic restarting of acute inflammation. 00:48:52.571 --> 00:48:56.631 Now you can see these active resolution processes, but that's just a function of the dynamics. 00:48:56.831 --> 00:49:00.011 Because you're constantly restarting, you're never fully healing, 00:49:00.051 --> 00:49:06.391 then you're seeing a resolution program that needs to kick in and stay on for a long period of time. 00:49:06.411 --> 00:49:09.971 And then you can call that now a resolution program because it's tied to the 00:49:09.971 --> 00:49:11.451 resolution of inflammation. 00:49:11.831 --> 00:49:18.011 But if your explanation of chronic inflammation as the result of starting up 00:49:18.011 --> 00:49:20.871 the process of acute inflammation, but is doing it repetitively. 00:49:21.691 --> 00:49:26.971 That would suggest that some timescale you should see transients in the chronic responses. 00:49:27.051 --> 00:49:29.451 Is that the case? I think it is now that people are looking. 00:49:29.691 --> 00:49:37.431 I think that often there is an inherent sort of, let's call it bias. 00:49:37.811 --> 00:49:41.011 You make a hypothesis, and the hypothesis is geared towards, 00:49:41.131 --> 00:49:43.731 let's say, looking at arms of the response that are downstream. 00:49:43.991 --> 00:49:46.911 Well, then, of course, you're going to be seeing the arms of the response that are downstream. 00:49:47.651 --> 00:49:51.451 This is why systems approaches like the ones we do are, I think, very necessary. 00:49:51.871 --> 00:49:56.991 So because we interrogate for the, we stay agnostic and we interrogate the entire 00:49:56.991 --> 00:50:00.011 process all the time at every time point that we study, 00:50:00.151 --> 00:50:08.731 we have a chance, an opportunity to actually see mechanisms that are acute being 00:50:08.731 --> 00:50:11.251 turned on. We also see the reverse phenomenon. 00:50:11.451 --> 00:50:15.731 We see a very rapid activation of processes that are thought to be more chronic. 00:50:15.831 --> 00:50:19.071 But again, they're in the context of also processes that are very acute, 00:50:19.151 --> 00:50:20.751 which I think is just a part of the hallmark. 00:50:21.071 --> 00:50:24.211 Yeah. And I mean, the building of dynamic networks or network representations, 00:50:24.851 --> 00:50:28.871 of these are also key because people tend to focus on single mediators. 00:50:28.991 --> 00:50:31.691 So you measure 30 mediators and you say, okay, I'm seeing a program. 00:50:31.871 --> 00:50:35.251 But of course, in order to say that you're seeing it, it has to pass a statistical 00:50:35.251 --> 00:50:38.071 test and if it doesn't pass the statistical test then you're not seeing it. 00:50:38.191 --> 00:50:41.731 But if you look at it out of the network, you all of a sudden find that it's there. Right. 00:50:42.831 --> 00:50:46.911 But also, if you look at these interactions in the positive and negative feedback 00:50:46.911 --> 00:50:52.371 loops, they are used and then distinguish establish a predefined component and 00:50:52.371 --> 00:50:53.251 a more adaptive component. 00:50:53.611 --> 00:50:56.631 Yes. So who's the mediator of the adaptive component? 00:50:58.676 --> 00:51:04.756 So the adaptive components are, I'm assuming that you're meaning the cells and 00:51:04.756 --> 00:51:08.036 the mediators that are characteristic of the adaptive immune response? 00:51:08.256 --> 00:51:10.516 Yeah, like T-cell mediator responses that you mentioned. 00:51:10.756 --> 00:51:14.516 Right. So some of the mediators are shared. 00:51:14.696 --> 00:51:19.796 So T-helper type 1 or T-helper type 2 are now, you know, Th17, 00:51:19.916 --> 00:51:23.876 and there's many other subsets that have evolved, but let's just for simplicity's 00:51:23.876 --> 00:51:26.696 sake, focus on the Th1 versus Th2. 00:51:26.876 --> 00:51:32.216 There's a set of mediators that are also being made by innate immune cells, 00:51:32.416 --> 00:51:37.696 but that happen to serve the program of driving the differentiation of, let's say. 00:51:41.256 --> 00:51:46.416 Specific subsets of T cells that have fairly specific T cell receptors that say, 00:51:46.496 --> 00:51:49.736 for example, might be specific for the particular pathogen you got infected 00:51:49.736 --> 00:51:56.636 with because it is efficient in the face of a long-lasting infection, 00:51:57.436 --> 00:52:00.816 to focus on just that infection rather than a generalized alarm that 00:52:00.816 --> 00:52:03.516 impacts many bystander cells 00:52:03.516 --> 00:52:06.776 and many other systems negatively right the initial 00:52:06.776 --> 00:52:11.836 the initial responses is fairly non-specific and there's a trade-off which is 00:52:11.836 --> 00:52:16.976 you're damaging your cells the trade-off on the one hand is a necessary price 00:52:16.976 --> 00:52:20.176 to pay but on the other hand it's part of the amplification loop because the 00:52:20.176 --> 00:52:23.636 damage that you're doing to the cells produces these damps which further amplifies 00:52:23.636 --> 00:52:26.696 and And so it's part of the structure. It's actually not just bystander damage. 00:52:26.896 --> 00:52:28.776 It is bystander damage, but it's 00:52:28.776 --> 00:52:34.276 also bystander damage that is part of the structure of the system, right? 00:52:37.436 --> 00:52:40.356 So that's okay within a range, but now after a certain point, 00:52:40.416 --> 00:52:41.516 you can't tolerate that anymore. 00:52:41.696 --> 00:52:47.836 The signaling aspect of the damage becomes secondary to the actual damage part of the damage. 00:52:47.976 --> 00:52:54.396 And so then you don't want to keep, You can't keep that going non-stop. 00:52:54.476 --> 00:52:56.956 It has to sort of segue to something else. 00:52:57.136 --> 00:53:01.136 So the system is already building up the potential to become focused, 00:53:01.216 --> 00:53:04.016 but you don't want to become focused too soon because that isn't intelligent. 00:53:04.256 --> 00:53:07.596 It's the equivalent of what happens in the vaccine setting. We vaccinate for 00:53:07.596 --> 00:53:09.996 flu. It's the wrong strain. 00:53:10.196 --> 00:53:15.976 And now we have no protection, right? We force the system to go in a certain direction. 00:53:15.976 --> 00:53:18.716 Infection a vaccine is nothing more than an 00:53:18.716 --> 00:53:22.076 adjuvant which activates the innate immune response and the antigen 00:53:22.076 --> 00:53:25.096 part which activates the adaptive part but that the 00:53:25.096 --> 00:53:27.836 system is a cascade working together so we force it to go in one 00:53:27.836 --> 00:53:31.736 direction with the vaccine but maybe we forced it in the wrong direction so 00:53:31.736 --> 00:53:35.556 now we have too much of a response for exactly the wrong thing and now the vaccine 00:53:35.556 --> 00:53:40.516 is not functional um in the but the thought is that it's still better than trying 00:53:40.516 --> 00:53:44.156 to do it by random coincidence and just activating the pre-existing clones that 00:53:44.156 --> 00:53:45.596 you have for that specific infection. 00:53:45.836 --> 00:53:49.836 But absent modern medicine, that's how you'd have to do it. You would have to. 00:53:51.727 --> 00:53:56.287 As soon as possible, but not too soon, segue over to a response that's as focused 00:53:56.287 --> 00:53:58.307 as possible to the actual problem that you have. 00:53:58.707 --> 00:54:06.267 Right. So, does that then also explain or at least suggest why at some point 00:54:06.267 --> 00:54:08.607 just bringing the brain as a control system? 00:54:08.607 --> 00:54:17.207 As I said, I think that the brain is an almost necessary control mechanism once 00:54:17.207 --> 00:54:22.687 you achieve a certain structure, a certain compartmentalization, a certain size. 00:54:23.467 --> 00:54:28.067 As soon as you have to optimize more than one function, it's not just get me 00:54:28.067 --> 00:54:32.067 away from this gradient or push me towards that other gradient or fight off 00:54:32.067 --> 00:54:35.727 that one bacterium. I now have to have many systems that need to be optimized. 00:54:35.847 --> 00:54:39.847 I need to trade off over a period of time. Maybe I'll trade off some liver function 00:54:39.847 --> 00:54:41.267 because the liver is very resilient. 00:54:42.167 --> 00:54:45.847 I might trade off some lung function, but, you know, how much, 00:54:45.847 --> 00:54:49.287 how much, you know, I could trade off some gut function, you know, 00:54:49.287 --> 00:54:52.607 but how much heart function am I willing to trade off? Right. 00:54:52.887 --> 00:54:56.187 And so on. I mean, and yet, and they all do. There's phenomena 00:54:56.187 --> 00:54:59.347 that happen in every one of those organs that involve things like 00:54:59.347 --> 00:55:02.147 stunning and hibernation where pathways are being turned 00:55:02.147 --> 00:55:05.247 off to to to limit damage to retain energy 00:55:05.247 --> 00:55:08.527 the system is is doing a lot of of 00:55:08.527 --> 00:55:12.687 adjustments to this right uh and 00:55:12.687 --> 00:55:18.127 my sense is that that would not be possible without uh the brain but it's also 00:55:18.127 --> 00:55:22.007 clearly possible at some level without the brain right so that the tissue is 00:55:22.007 --> 00:55:24.987 able to do it but then to do it truly in a coordinated fashion you need the 00:55:24.987 --> 00:55:28.547 brain You could do it with predefined rules, 00:55:28.867 --> 00:55:33.367 I could claim, as long as the system doesn't show histories and memory. 00:55:34.307 --> 00:55:38.607 But if every challenge to the system leaves a trace in memory, 00:55:38.927 --> 00:55:43.267 then your predefined rules by necessity have to fail because they can never 00:55:43.267 --> 00:55:46.067 take into account all these varying set points, right? 00:55:46.167 --> 00:55:49.287 So maybe this is the main reason why you would need a brain, 00:55:49.447 --> 00:55:55.007 but that would suggest then that your brain has to have a representation of 00:55:55.007 --> 00:55:57.087 these set points, of these changing set points. 00:55:57.267 --> 00:56:01.087 So is there any data that would support that? 00:56:02.304 --> 00:56:08.944 Yeah, I think it does. I mean, in fact, just even observing the system and measuring 00:56:08.944 --> 00:56:15.224 key mediators, you can actually see a sense of this early hysteresis, 00:56:15.324 --> 00:56:16.664 which settles into a trajectory. 00:56:16.884 --> 00:56:21.644 In fact, we've got a study on this coming out very soon, hopefully, 00:56:21.824 --> 00:56:28.264 I mean, submitting it soon, that actually discovers in trauma patients or using trauma patients, 00:56:28.304 --> 00:56:31.644 but something that we find in other systems as well a regulatory architecture 00:56:31.644 --> 00:56:34.524 that we infer from having collected the data over 00:56:34.524 --> 00:56:37.964 time and modeled it as a network um and then 00:56:37.964 --> 00:56:43.764 encoded that hypothesis into a sort of a boolean model and and then playing 00:56:43.764 --> 00:56:47.384 it forward and she's seeing that many qualitative and quantitative features 00:56:47.384 --> 00:56:50.864 of the system become reproduced from this and it's a network that's bouncing 00:56:50.864 --> 00:56:55.444 up and down initially so it's hysteresis and it's figuring out it's it's it's reacting it's It's, 00:56:55.524 --> 00:56:59.424 of course, driven by the starting points of the system, which are individual specific. 00:56:59.704 --> 00:57:03.044 So people come into this with different initial set points. 00:57:03.204 --> 00:57:07.744 But if you run this simulation across time, you will see an early hysteresis, 00:57:07.844 --> 00:57:09.084 and then it settles on a trajectory. 00:57:09.184 --> 00:57:16.664 And you can map that to, I think you can map that to what might be happening 00:57:16.664 --> 00:57:22.444 in different organs and how the system responds as a whole. Right. 00:57:22.484 --> 00:57:33.464 But now the brain control, how does the brain represent that system that is prone to get inflamed? 00:57:34.964 --> 00:57:42.264 What's the resolution of it? So it seems like at least two key inflammatory 00:57:42.264 --> 00:57:46.504 mediators that happen to also be ones that drive this positive feedback loop 00:57:46.504 --> 00:57:54.344 are expressed in the brain in settings where inflammation is happening at a peripheral organ. 00:57:54.484 --> 00:57:58.844 Either peripheral, like a peripheral organ alone, where you can give the noxious 00:57:58.844 --> 00:58:02.804 stimulus directly into that organ, and you can induce an inflammatory response 00:58:02.804 --> 00:58:05.484 that is not just spilling over systemically internally. 00:58:06.140 --> 00:58:10.820 But is staying fairly localized, the brain in the area that also happens to 00:58:10.820 --> 00:58:14.220 control the function, a key function of, let's say, that organ, 00:58:14.300 --> 00:58:20.600 in this case, the lung, is expressing this inflammatory meter. 00:58:20.660 --> 00:58:22.640 It's present in the lung. It's present in the brain. 00:58:22.780 --> 00:58:25.300 It's not just present everywhere. So it's not a giant diffusion issue. 00:58:25.620 --> 00:58:28.960 And the region of the brain also 00:58:28.960 --> 00:58:32.420 happens to be the one that regulates a particular function of that organ. 00:58:32.540 --> 00:58:35.040 And you can measure that that function becomes disturbed. Dr. 00:58:35.040 --> 00:58:38.100 That's the nucleus tract desolator. Yes, the nucleus tract desolator. 00:58:38.300 --> 00:58:43.360 Dr. But do you imagine, as we have a somatosensory map of, let's say, 00:58:43.360 --> 00:58:46.020 the things we touch or in the properties of our muscles, 00:58:46.360 --> 00:58:51.640 you would imagine that I have a similar map representing all my organs and their 00:58:51.640 --> 00:58:53.300 inflammatory state? Right. 00:58:53.680 --> 00:58:58.520 One could imagine even interesting, one could take a little flight of fancy 00:58:58.520 --> 00:59:06.040 and say say, things like acupuncture or acupressure that are based on the concept 00:59:06.040 --> 00:59:08.340 of meridians are doing that. 00:59:08.660 --> 00:59:12.580 It's a manual way of creating that same thing. You create pressure at a distal 00:59:12.580 --> 00:59:16.640 location, which sends a signal to the brain, which can impact the liver, right? 00:59:17.420 --> 00:59:22.360 In martial arts, you have the ability to potentially strike a particular location 00:59:22.360 --> 00:59:27.160 in a peripheral area and have that translate to damage to the liver or the heart. 00:59:27.300 --> 00:59:34.080 So intuitively or empirically, people over the years have figured out that you 00:59:34.080 --> 00:59:37.540 can actually even use these methods for good or for bad. 00:59:37.940 --> 00:59:41.480 And so I think that is in fact how the system is wired. 00:59:41.560 --> 00:59:50.780 The system is wired so that there is a sensation of damage or dysfunction in a particular location. 00:59:51.420 --> 00:59:56.400 There's an impact there's a sensation of that in the brain in a particular area 00:59:56.400 --> 01:00:00.060 and then presumably if that's above a certain threshold there's a secondary 01:00:00.060 --> 01:00:03.180 activation of inflammation in the peripheral organ. 01:00:04.069 --> 01:00:07.429 One would like to believe that within a range, this is something that's evolutionarily 01:00:07.429 --> 01:00:08.849 beneficial for some reason. 01:00:08.929 --> 01:00:14.309 As I said, either that's because it's doing it in anticipation of there being 01:00:14.309 --> 01:00:15.749 a dysfunction that's going to 01:00:15.749 --> 01:00:19.089 occur in that organ or an infection that's going to occur in that organ. 01:00:19.389 --> 01:00:24.949 And so there's a pre-positioning of defenses or even a pre-starting of a healing program. 01:00:25.389 --> 01:00:28.169 But also just be an artifact, right? Or it could be an artifact. 01:00:28.289 --> 01:00:29.729 You have multiple somatosensory maps. 01:00:30.089 --> 01:00:35.549 Yes. And maybe, let's say, delivering one map ends up to the lower arm in another map. 01:00:35.709 --> 01:00:40.049 But in the brain, there goes so much activity, it can spill over. 01:00:40.469 --> 01:00:44.769 I could totally see that happening as well. And so then maybe that's when it 01:00:44.769 --> 01:00:50.629 becomes pathological, because now you're getting triggering for completely stochastic 01:00:50.629 --> 01:00:53.549 reasons or just reasons that have to do with proximity. 01:00:53.749 --> 01:00:58.789 And now you get a secondary response somewhere else that now is no longer good. Good. 01:00:59.169 --> 01:01:03.989 I would argue that when it does that, because of the closing of the loops, 01:01:04.169 --> 01:01:09.089 you end up having a compensatory response also driven by the brain to try to address that. 01:01:09.189 --> 01:01:12.529 Now, maybe that compensation is too much or too little, and that causes another 01:01:12.529 --> 01:01:14.389 problem. Maybe that's how things ripple. 01:01:15.569 --> 01:01:21.009 The point is, it's very interesting that in talking to clinical colleagues, 01:01:21.109 --> 01:01:24.949 so for example, a key phenotype that happens following severe trauma, 01:01:24.989 --> 01:01:30.049 or that actually happens following underlying sepsis infection is that you get 01:01:30.049 --> 01:01:31.229 a severe blood pressure drop. 01:01:31.369 --> 01:01:34.529 In trauma, you get it because you're bleeding. In sepsis, you get it through 01:01:34.529 --> 01:01:37.289 secondary inflammatory mechanisms that create a blood pressure drop. 01:01:37.469 --> 01:01:42.009 The typical clinical response is to give fluids to raise the blood pressure 01:01:42.009 --> 01:01:44.209 or to give pressors to raise the blood pressure. 01:01:44.909 --> 01:01:47.189 Because there's going to be, of course, an impact on the heart, 01:01:47.289 --> 01:01:48.809 they're going to use inotropes as well. 01:01:50.689 --> 01:01:54.829 But one might imagine that But within a range, it would be best to leave the 01:01:54.829 --> 01:01:58.209 system alone because the sensation of the blood pressure drop is itself triggering 01:01:58.209 --> 01:01:59.709 secondary corrective responses. 01:01:59.929 --> 01:02:05.029 The flooding of the system with information driven by an outside agent actually 01:02:05.029 --> 01:02:07.209 ends up confusing the system. 01:02:07.309 --> 01:02:10.929 The system now is unable to respond appropriately because it's looking for a 01:02:10.929 --> 01:02:12.369 set of cues that it just doesn't find. 01:02:13.540 --> 01:02:17.360 And now one could argue that critical illness is that. Because critical illness 01:02:17.360 --> 01:02:21.200 cannot show up if there was no intensive care unit, if there was no, 01:02:21.320 --> 01:02:25.160 I mean, I'm not in any way trying to say that we shouldn't have medical care, 01:02:25.260 --> 01:02:31.160 but certain phenotypes are a consequence of the medical intervention. 01:02:31.160 --> 01:02:32.720 Well, I think that's an important observation, right? 01:02:32.780 --> 01:02:36.800 Because as long as you don't understand this complex network nature of the system 01:02:36.800 --> 01:02:40.620 where you're chasing symptoms, we might be only further destabilizing it as 01:02:40.620 --> 01:02:44.240 opposed to helping it to get back within the range of normal operation. 01:02:44.440 --> 01:02:47.820 And I get a sense from my clinical colleagues that they often feel like that. 01:02:48.120 --> 01:02:52.560 Our study on the survivors versus non-survivors, which was followed of trauma, 01:02:52.820 --> 01:02:56.880 which was followed by another study we published recently, where we use that 01:02:56.880 --> 01:03:03.160 population to discover novel genotypes associated with survival and non-survival. 01:03:04.260 --> 01:03:09.200 Suggests the possibility that some percent of the population is wired from the 01:03:09.200 --> 01:03:12.120 beginning to have this very rapid feed-forward inflammation, 01:03:12.400 --> 01:03:16.340 which in the context of, say, severe traumatic injury, will lead to death. 01:03:16.560 --> 01:03:21.040 The suggestion is that, and of course that is ethically scary, 01:03:21.200 --> 01:03:28.420 because the suggestion is that as things are, it will simply not be possible to rescue those people. 01:03:28.920 --> 01:03:34.780 The hope would be that the discovery of those early pathways that we've done 01:03:34.780 --> 01:03:38.180 through network analysis might lead to targeted interventions It can be given 01:03:38.180 --> 01:03:40.220 very early to reverse that, to change that. 01:03:40.700 --> 01:03:44.360 Those pathways, by the way, are not, again, nothing in inflammation is ever 01:03:44.360 --> 01:03:48.140 just inherently harmful. Those pathways are pathways that would protect you from infection. 01:03:48.340 --> 01:03:54.440 So in normal daily life, the fact that you are overly sensitive sets you up 01:03:54.440 --> 01:03:57.360 for doing way better in terms of dealing with normal infections. 01:03:57.400 --> 01:04:02.280 But now at the wrong time, in the wrong place, with a severity of injury above 01:04:02.280 --> 01:04:05.680 a certain threshold, those genetics set you up for... 01:04:06.662 --> 01:04:07.822 Progressive inflammation and 01:04:07.822 --> 01:04:12.742 death but for those in those situations your only hope is to completely. 01:04:13.302 --> 01:04:16.782 Block communication between organs right so 01:04:16.782 --> 01:04:19.782 that would be that's a very interesting point so right rather than i mean i'm an immunologist 01:04:19.782 --> 01:04:23.142 so of course my normal solution is immune but one one 01:04:23.142 --> 01:04:26.802 could imagine that an appropriate uh stimulus 01:04:26.802 --> 01:04:29.802 given centrally at the at the brain level could 01:04:29.802 --> 01:04:32.722 in fact accomplish that meaning 01:04:32.722 --> 01:04:35.462 allow the allow the local environment to do 01:04:35.462 --> 01:04:39.462 its infection fighting thing if it can while stopping 01:04:39.462 --> 01:04:45.442 the message that says keep keep cascading positive feedback yeah i agree the 01:04:45.442 --> 01:04:50.142 key is of course identifying those patients now we now have a set of um seven 01:04:50.142 --> 01:04:55.382 single nucleotide polymorphisms that are interesting because they're not a single 01:04:55.382 --> 01:04:57.322 one of them is directly involved with inflammation, 01:04:57.562 --> 01:05:02.842 as we can tell, but are more with tissue health or resilience, 01:05:02.922 --> 01:05:09.882 if you will, we're completely predictive of the non-survivor phenotype. 01:05:10.002 --> 01:05:14.902 This needs to be validated again, because we have overall only about 5% of patients 01:05:14.902 --> 01:05:19.462 will end up being non-survivors in terms of people that make it into the intensive care unit. 01:05:19.542 --> 01:05:22.402 It's a larger percent if you look at severely injured patients that just are 01:05:22.402 --> 01:05:26.562 overwhelmingly injured, right? But but 95% of patients can survive. 01:05:26.862 --> 01:05:36.242 So the idea is that, yeah, if one had the right biomarkers and one had the right 01:05:36.242 --> 01:05:39.322 therapy that could be targeted in a very precise fashion. 01:05:40.602 --> 01:05:41.962 That should be quite doable. 01:05:42.182 --> 01:05:46.082 Right, exactly. Yes. So the other thing is now is the brain involved. 01:05:46.222 --> 01:05:49.402 The brain is controlling stuff, so it can be more complex. 01:05:51.702 --> 01:05:55.862 Contextualized perturbations to the system. but I'm going to pay a price because 01:05:55.862 --> 01:05:57.182 the brain goes to screw it up. 01:05:58.210 --> 01:06:02.610 Yes. So psychological stress. So one thing that happens already that can be 01:06:02.610 --> 01:06:06.230 observed in patients that are trauma patients, even if it's not traumatic brain 01:06:06.230 --> 01:06:08.810 injury, where there's of course a direct impact to the brain, 01:06:08.910 --> 01:06:11.110 is that you get into a kind of delirium state. 01:06:11.410 --> 01:06:16.450 There's a cognitive decline that is seen in severely injured patients. 01:06:16.810 --> 01:06:19.590 So that tells you the brain is in fact paying a price. 01:06:20.070 --> 01:06:23.630 Whether it's the assumption I think before was that it's an indirect process 01:06:23.630 --> 01:06:27.990 that has to do with the fact there's overwhelming inflammation, 01:06:28.030 --> 01:06:29.890 maybe a breakdown in the blood-brain barrier. 01:06:30.090 --> 01:06:34.170 But one could argue that one way in which you achieve that is because the brain 01:06:34.170 --> 01:06:36.630 is working overtime to try to regulate the inflammatory response, 01:06:36.770 --> 01:06:41.010 or it's getting now many centers activating with these inflammatory mediators 01:06:41.010 --> 01:06:44.510 that are both neurotransmitters and inflammatory mediators and have this positive 01:06:44.510 --> 01:06:45.350 feedback characteristic. 01:06:45.390 --> 01:06:48.630 So they rapidly spin up out of control in multiple places. 01:06:49.550 --> 01:06:53.650 Then one could imagine that could lead to at least a temporary cognitive impairment. 01:06:53.650 --> 01:06:59.550 One could also imagine that if over a long period of time one has repeated stresses, 01:06:59.750 --> 01:07:04.670 repeated infections, repeated traumas, that the system again becomes overwhelmed 01:07:04.670 --> 01:07:07.430 and that sets you up for a chronic neurodegenerative disease. 01:07:07.730 --> 01:07:11.530 But I want to push the test scale, the causation in a direction. 01:07:11.730 --> 01:07:17.190 Because yes, there's a lot of information that information leads to neuropathology, right? 01:07:17.210 --> 01:07:20.670 For Alzheimer's, Parkinson's disease, there are many examples, right? 01:07:20.750 --> 01:07:23.970 Or enough examples. but maybe it 01:07:23.970 --> 01:07:27.450 can go the other way around as well that mental states rebuilt 01:07:27.450 --> 01:07:30.250 by the brain start to actually have an impact on 01:07:30.250 --> 01:07:33.150 the inflammatory states of organs in the body yes that 01:07:33.150 --> 01:07:36.350 in the end lead to your demise yes no and again that 01:07:36.350 --> 01:07:39.330 that is a been very actively tested and 01:07:39.330 --> 01:07:42.350 it's a very major area of not just investigation 01:07:42.350 --> 01:07:46.710 but now of direct clinical application there are companies that are directly 01:07:46.710 --> 01:07:54.250 stimulating the brain to be an an anti-inflammatory mechanism or therapy for 01:07:54.250 --> 01:08:00.010 things like sepsis or rheumatoid arthritis or other sort of clearly inflammatory diseases. 01:08:00.250 --> 01:08:02.870 And it's not just by coincidence. It's because of this hypothesis, 01:08:03.030 --> 01:08:05.310 because of the data behind it and so forth. 01:08:05.410 --> 01:08:12.270 What mental states can lead then to or amplify sepsis, aggravates as an example? 01:08:12.330 --> 01:08:16.810 What mental states, would you call them stress, psychological stress. 01:08:17.130 --> 01:08:22.050 Or would you call them something else? I think that has been very understudied. 01:08:22.070 --> 01:08:26.330 The problem with sepsis is that although it is very much an acute inflammatory 01:08:26.330 --> 01:08:29.870 process and it can very rapidly spin up and out of control, 01:08:30.090 --> 01:08:34.990 the clinicians typically don't see the patient until that patient has been incubating 01:08:34.990 --> 01:08:39.470 this infection for some period of time, which can vary before they show up with 01:08:39.470 --> 01:08:42.310 severe enough symptoms to the intensive care unit. 01:08:42.310 --> 01:08:47.650 So it's very tough to be able to, to make that study in trauma. 01:08:47.970 --> 01:08:54.210 The problem is that almost no trauma has zero impact on the brain to start with, right? 01:08:55.203 --> 01:08:58.883 So even if it's not a direct traumatic brain injury, there's the, 01:08:59.063 --> 01:09:04.263 of course, the massive sensation of the traumatic event. 01:09:04.383 --> 01:09:08.763 And then there's, of course, almost impossible to have the lack of any kind 01:09:08.763 --> 01:09:13.963 of anatomical impact on the head region and have an injury severe enough to 01:09:13.963 --> 01:09:16.823 actually be having the symptoms one talks about. 01:09:16.923 --> 01:09:20.563 So it's, again, one of these very tough situations where I think it's there. 01:09:20.643 --> 01:09:24.803 I think it does do what you say, where someone pre-stressed. you 01:09:24.803 --> 01:09:27.583 can you could do epidemiologic studies i think they have been done 01:09:27.583 --> 01:09:30.823 but again there's so many factors that go into that um 01:09:30.823 --> 01:09:33.963 that and you know there is 01:09:33.963 --> 01:09:38.143 this very interesting um brain related 01:09:38.143 --> 01:09:45.543 uh or apparently brain related uh study in sepsis that looks at something that 01:09:45.543 --> 01:09:51.163 you would think would be quite a negative thing so smoking so it turns out that 01:09:51.163 --> 01:09:56.143 because Because nicotine itself can trigger, 01:09:56.363 --> 01:10:00.623 you know, the nicotinic pathway can trigger anti-inflammatory mechanism. 01:10:00.923 --> 01:10:04.483 Sometimes smokers actually are doing better in sepsis. You would think it'd 01:10:04.483 --> 01:10:06.983 be the other way around since they're having compromised lung function. 01:10:07.163 --> 01:10:09.823 Right. So, of course, one wouldn't recommend people to start smoking. 01:10:09.963 --> 01:10:14.743 But it's an intriguing sort of hypothesis. 01:10:14.743 --> 01:10:23.743 Hypothesis um i think that as i said i think it would be quite likely that being in chronic stress. 01:10:24.383 --> 01:10:27.123 Will will set you up for i mean it's known that being 01:10:27.123 --> 01:10:30.703 in chronic stress will set you up for infection that that's sort of known whether 01:10:30.703 --> 01:10:35.263 the epidemiology has been done to say that you could progress from that to full-blown 01:10:35.263 --> 01:10:39.283 sepsis i'm not i i don't think consequence of what you're saying now we're told 01:10:39.283 --> 01:10:45.043 the smoker example in some sense collectively we make this naive assumption. 01:10:45.883 --> 01:10:49.303 That the healthy state is zero 01:10:49.303 --> 01:10:52.843 perturbation of the system it's this homoestatic view again we're in stasis 01:10:52.843 --> 01:10:59.103 but it is misguided because it's i was stuck it's a it's a dynamic system it's 01:10:59.103 --> 01:11:03.103 a continuous change it's continuous change that maintains the healthy state 01:11:03.103 --> 01:11:06.503 in a range appropriate responsiveness is held. 01:11:06.583 --> 01:11:10.083 We showed that. So before we did all the modeling, we showed in trauma patients 01:11:10.083 --> 01:11:12.183 and also in experimental animals, 01:11:12.423 --> 01:11:17.623 the large animal swine model of severe injury and hemorrhage, 01:11:17.723 --> 01:11:23.283 that if you didn't mount an appropriate, adequately robust, say, 01:11:23.423 --> 01:11:24.783 inflammatory response, 01:11:25.143 --> 01:11:32.283 you would be a non-survivor or you would be an animal that is not amenable to resuscitation. 01:11:32.283 --> 01:11:36.563 So a mediator that you would say oh no look there's an inflammatory response 01:11:36.563 --> 01:11:39.503 they might they're probably going to do worse actually they're the ones that 01:11:39.503 --> 01:11:43.243 are doing well because they're it's a surrogate it's a proxy for responsiveness 01:11:43.243 --> 01:11:47.983 you can show that by measuring um you know norepinephrine you can you can measure 01:11:47.983 --> 01:11:50.243 other and they track with this so, 01:11:50.703 --> 01:11:54.703 there's a the inflammatory responsiveness is just another way of saying responsiveness. 01:11:55.870 --> 01:12:00.510 So, look, Jeroen, so for me, this is all fantastic also because I'm learning a lot. 01:12:00.650 --> 01:12:06.510 And it's also beautiful to see that this compartmentalization of a naively imposed 01:12:06.510 --> 01:12:10.790 on the system, like distinguishing brain from body from immune. 01:12:10.950 --> 01:12:13.310 This has been not very helpful, right? 01:12:13.510 --> 01:12:15.610 That's where these are very intensely coupled networks. 01:12:16.210 --> 01:12:20.250 So, now you're in this domain of immunology for a long time. 01:12:20.250 --> 01:12:23.410 You also have really been sort of advancing and 01:12:23.410 --> 01:12:26.290 struggling to bring new concepts and ways of thinking 01:12:26.290 --> 01:12:32.030 into the field so if we would like to follow in in in in that tradition that 01:12:32.030 --> 01:12:38.710 you represent what would be your arm's law that we have to adhere to um i don't 01:12:38.710 --> 01:12:43.010 know that i've ever would ever see myself as positing something like that i 01:12:43.010 --> 01:12:45.010 would say that that the best thing i can 01:12:45.050 --> 01:12:54.170 say is that inflammation as a communication network is something that needs 01:12:54.170 --> 01:12:59.770 to be looked at in pretty much any system that you're trying to study biologically. 01:12:59.990 --> 01:13:06.510 I don't really have a law like these are the exact underlying structural or 01:13:06.510 --> 01:13:10.510 functional motivations of biology or something like that. 01:13:10.630 --> 01:13:15.750 I'm just not at a place where I can say anything like that. The practice of 01:13:15.750 --> 01:13:19.250 doing science, the practice of gaining knowledge about this system. 01:13:19.610 --> 01:13:24.990 Well, then that's much simpler. Yeah. I would say always interact with people 01:13:24.990 --> 01:13:29.370 from a different discipline and that think differently from you and then try 01:13:29.370 --> 01:13:32.410 to integrate as much as possible. 01:13:32.550 --> 01:13:34.810 Don't have preconceived notions. 01:13:35.130 --> 01:13:41.030 I would say that is true. Yes. Okay. So now I'm going to visit you in four years' 01:13:41.130 --> 01:13:43.570 time out there in Pittsburgh. 01:13:46.390 --> 01:13:52.630 I'm going to check the progress of research. As you know, research is hypothesis-driven. 01:13:53.350 --> 01:13:58.050 So what's the hypothesis that you want to see confirmed in that four-year time window? 01:13:58.050 --> 01:14:02.670 So these studies that we've done that suggest now this temporal sequence of 01:14:02.670 --> 01:14:09.270 inflammatory activation bring up the automatic hypothesis that the innervation 01:14:09.270 --> 01:14:16.670 of those organs that are being activated in sequence has something to do with 01:14:16.670 --> 01:14:17.710 that inflammatory response. 01:14:17.990 --> 01:14:22.570 So then the logical study is studies in which you're doing selective denervation 01:14:22.570 --> 01:14:27.550 to the bottleneck organs, if you will. So, you know, selectively denervate. 01:14:28.130 --> 01:14:31.570 So for example, the spleen, you know, selectively, it's one of the, 01:14:31.570 --> 01:14:34.970 it's essentially, we're seeing in mice, at least that that seems to be the place 01:14:34.970 --> 01:14:35.470 where inflammation occurs. 01:14:36.965 --> 01:14:41.105 Reaches its peaks the soonest. The spleen is known to be, of course, very innervated. 01:14:41.225 --> 01:14:47.785 So selectively denervate the spleen, collect the time course data, 01:14:48.025 --> 01:14:50.025 run the network analyses, and 01:14:50.025 --> 01:14:53.505 see whether the networks that you've previously seen are now collapsed. 01:14:53.505 --> 01:14:57.245 The prediction of the spleen is the hub of inflammation? 01:14:57.705 --> 01:15:03.525 For this particular mouse model. So in this particular strain of mice that's 01:15:03.525 --> 01:15:07.285 tuned to be very inflammatory and to this particular stimulus. 01:15:07.725 --> 01:15:11.805 Now we have an entire set of data that I didn't even talk about today where 01:15:11.805 --> 01:15:16.445 we subjected the same mice, the same two types of mice, to experimental trauma hemorrhage. 01:15:16.445 --> 01:15:21.185 Because it turns out that not the beauty of this is the same receptor that's 01:15:21.185 --> 01:15:25.905 being used to sense damage associated molecular pattern molecules in the case 01:15:25.905 --> 01:15:30.765 of trauma is the one that also is being sensed for lipopolysaccharide in the 01:15:30.765 --> 01:15:34.205 case of sepsis so so we could compare the two mice. 01:15:35.385 --> 01:15:39.905 Strains across time and across all the the organs right but now the stimulus 01:15:39.905 --> 01:15:42.505 is quite different It has a different characteristic. 01:15:42.705 --> 01:15:51.085 It's not a rapidly peak-shaped, you know, input influx of a very strong bacterial immunostimulant. 01:15:51.165 --> 01:15:54.965 It's now a combination of trauma with hemorrhage and secondary mechanisms. 01:15:55.285 --> 01:16:00.445 And all these organs do fail in the critically ill patients that have that. 01:16:00.465 --> 01:16:04.745 How do you summarize it in a 10-word prediction we can print on a T-shirt? 01:16:05.165 --> 01:16:09.065 For what's going to happen in the trauma hemorrhage? I would say that in the 01:16:09.065 --> 01:16:12.605 trauma hemorrhage, we were going to probably see a much more central early role 01:16:12.605 --> 01:16:18.165 for the gut, which we saw a bit later in the sort of sepsis model. 01:16:18.845 --> 01:16:24.565 But I think the bigger prediction is more that we will see networks collapsing 01:16:24.565 --> 01:16:29.145 when we denervate the bottleneck organ. 01:16:29.205 --> 01:16:32.705 Let's say the first organ that matters. We will see downstream networks collapsing. 01:16:32.925 --> 01:16:37.785 And that if we do the control study where we, let's say, denervate the last 01:16:37.785 --> 01:16:43.385 organ or somewhere in the middle, we're only going to see a partial collapse of those networks. Yes. 01:16:43.905 --> 01:16:47.145 Wonderful. Jeroen Bodevoort, thank you very much for this conversation. 01:16:47.525 --> 01:16:51.985 Thank you very much for having me on this podcast and for inviting me to BCBT. 01:16:52.305 --> 01:16:54.645 You're welcome. Terrific. Go back anytime. 01:16:57.005 --> 01:17:02.885 The CSN podcast was produced by the Convergent Science Network of Biometrics 01:17:02.885 --> 01:17:09.245 and Biohybrid Systems, a project funded by the European Sevens Research Framework Program. 01:17:10.805 --> 01:17:16.145 For more interviews, recorded lectures, or upcoming conferences in the field 01:17:16.145 --> 01:17:22.405 of biometrics and biohybrid systems, go to csnnetwork.eu. 01:17:22.320 --> 01:17:30.800 Music.