Listeners:

Top listeners:

00:00 00:00

Go to album

Paul Verschure on consciousness and distributed adaptive control CSN Podcasts
Edvard Moser on grid cells and entorhinal cortex CSN Podcasts
Giacomo Rizzolatti on mirror neurons and action understanding CSN Podcasts
Robert Axelrod on game theory and prisoner's dilemma CSN Podcasts
Adrian Owen on disorders of consciousness and vegetative state CSN Podcasts
Jonathan Whitlock on markerless motion capture and posterior parietal cortex CSN Podcasts
Luis Puelles on neuroanatomy and prosomeric model CSN Podcasts
Zoltan Molnar on subplate neurons and cortical development CSN Podcasts

Yoram Vodovotz on inflammation and immune system

Episode 13 15.03.2019

PLAY EPISODE

Season 2019

0 Followers 13 Episodes

Description

What if inflammation is not a disease but a communication system , one that becomes pathological only when its own signaling cascades spiral beyond the control mechanisms that normally contain them? Immunologist Yoram Vodovotz reframes inflammation as the body’s intermediate-timescale information network, connecting injury detection to healing response, and explains why understanding its failure requires thinking at the level of whole-organism control rather than individual molecules. Subscribe for more from the Convergent Science Network podcast series. Yoram Vodovotz joins Paul Verschure and Tony Prescott to trace inflammation from its origins in single-cell stress responses through multi-organ coordination to the neural regulation of immune function via the vagus nerve. At its core, inflammation is communication: molecular pathways that connect an initial insult to a coordinated response. The problem arises when these same communication molecules , cytokines, damage-associated molecular patterns, coagulation factors , cross thresholds and become causative agents of disease rather than mere markers. Vodovotz illustrates this with examples ranging from mosquitoes fighting malaria parasites using the same inflammatory pathways as their human hosts to the deadly positive feedback loop between coagulation and inflammation following traumatic injury. The conversation builds toward a systems-level understanding of how organs mount distinct inflammatory responses on different timescales, with gut and lung tissues maintaining high thresholds against constant environmental exposure while internal organs respond immediately to any bacterial signal. Vodovotz argues that predefined organ-specific response patterns, shaped by evolutionary pressures, interact with neural control circuits, particularly vagal pathways, that monitor and modulate inflammation across the whole organism. When genetic variability makes an individual overly sensitive or the threat exceeds containment capacity, the system fails and inflammation becomes the disease itself. Key topics include why inflammation may underlie all disease states, how autopoiesis and homeostatic self-maintenance connect to inflammatory control, the evidence for cross-organism transfer of inflammatory information between parasite vectors and hosts, why vagus nerve stimulation can outperform systemic drugs in treating inflammatory disease, and how computational models of organ-specific inflammatory dynamics could guide therapeutic intervention. Part of the Convergent Science Network podcast series from the BCBT Summer School.

Tagged as:
Disease immune system inflammation Inflammatory Vagus Nerve

About the author

CSN Podcasts

Both the triumphs of humanity and its most evil deeds have resulted from collaboration. In a time where humanity is required to aspire to the former and minimize the latter, the question arises of how collaboration arises and why it fails. Surprisingly, this phenomenon, so central to who we are, is not well understood. Hence, a collaborative effort is required to understand collaboration in its full biological, psychological, sociological, cultural, and economic complexity and to translate this understanding into operational impact. This series of podcasts is one step toward achieving these complementary goals. The Collaboration Podcast presents interviews with people who are central orchestrators of collaboration in various domains including business, government, science, art, health, sustainability, and the military. The discussions were conducted by Prof. Dr. Paul F.M.J. Verschure and members of the Program Advisory Committee of the Ernst Strungmann Forum on Collaboration (https://www.esforum.de/forums/ESF32_Collaboration.html) during 2021 and had the goal to sketch a map of opportunities, challenges, and obstacles in human collaboration. The forum took place in May 2022, and now we would like to share this series of interviews with a broader audience. The full report of the Forum will be published in 2023 by MIT Press. The podcast was produced by the Convergent Science Network (https://www.convergentsciencenetwork.org/). Context: The stability of social systems depends critically on realizing sustainable methods of “collaboration,” yet how and by which means collaboration is achieved is not clearly understood; neither are the conditions or processes that lead to its breakdown or failure. Collaboration can be understood as cooperation between agents toward mutually constructed goals. Part of the reason for our lack of understanding is that the phenomenon of collaboration is, by nature, a highly multidisciplinary problem, and effective research into its complexities has been difficult to achieve across the broad range of scientific and technical disciplines involved. The need for a fundamental understanding of collaboration, however, has become increasingly important. Not only does humankind demand answers as it attempts to address critical challenges at multiple scales (e.g., climate change, migration, enhanced automation, social and economic inequality), but ever-increasing technological and economic means of interconnecting people and societies are disrupting long-established, familiar patterns of how we interact. Radical technological changes that are ongoing have the potential to reshape collaboration in ways that are currently hard to predict or influence (e.g., by altering configurations in interaction, information creation, and modes of communication). On one hand, such changes could disrupt hitherto stable forms of collaboration by affecting critical communication channels and traditional roles, as can be observed in the rapidly changing patterns in governance, commerce, and social interaction. Conversely, technology could lead to the emergence of novel, successful forms of collaboration that deviate from traditional “hierarchical” architectures. Evidence of this can be seen in areas as diverse as highly automated manufacturing plants, the open science movement, collaborative software repositories, user-centered services, and the sharing of economy-based modes of organization. Without a fundamental understanding of the mechanisms, processes, and boundary conditions of collaboration, it is not possible to evaluate or predict which of these possible scenarios are sustainable or even plausible. The Forum “How Collaboration Arises and Why it Fails” (May 8–13, 2022, Location: Frankfurt am Main, Germany) Chairs: Andreas Roepstorff and Paul Verschure Program Advisory Committee: Jenna Bednar, Julia R. Lupp, Bhavani R. Rao , Andreas Roepstorff, Ferdinand von Siemens, and Paul Verschure

Timestamp

00:00:03 - This is the Convergent Science Network podcast. Leading researchers in the domain
00:00:10 - of neuroscience, brain theory and technology are interviewed by Paul Verschoor and Tony Prescott.
00:00:20 - So this is Paul Verschoor with the Convergent Science Network podcast for the
00:00:25 - Barcelona Cognition, Brain and Technology Summer School of 2018.
00:00:31 - And I'm here with Joram Vodovic. Welcome, Joram, to our summer school.
00:00:36 - You spoke about the inflammatory response, inflammation, and also how the body responds to that.
00:00:45 - So how do you think the notion of inflammation is informative with respect to
00:00:54 - questions around, let's say, control and how even the brain might be engaging with the body.
00:01:00 - Well, thanks, Paul. I think that at some level, it is just natural to think
00:01:08 - about that a process that can be as destructive as inflammation needs to be controlled.
00:01:13 - So the organism is wired to be able to respond to cues to cues that can be dangerous
00:01:25 - with an inflammatory response.
00:01:28 - And maybe even cues that are just stressful. And then that has to be resolved
00:01:33 - and reset and be available to be used again.
00:01:38 - And so one thing that's interesting that we find is that inflammation is regulated
00:01:45 - at a very local level, at the cellular level,
00:01:49 - that does not immediately appear to require any kind of additional neural control.
00:01:55 - But at the same time, when we look structurally at the way the neural mechanisms,
00:02:00 - all evidence points to pathways regulated by the vagus nerve that are probably
00:02:09 - involved in sort of minute-to-minute regulation of inflammation,
00:02:14 - to the point that you can actually target that
00:02:17 - mechanism to uh improve or
00:02:23 - reduce the inflammatory response in uh fairly
00:02:26 - intractable inflammatory disease states in a way that's much more powerful and
00:02:32 - potent than simply administering drugs uh systemically with that now you you
00:02:38 - only jump to the conclusions before we you even have done the introductory parts, right?
00:02:43 - Because also in your talk, you indicated that in your view, inflammation is underlying the.
00:02:52 - Maybe all diseases or is involved in all diseases in some form.
00:02:56 - Yes, I think so. So it's very global, but would it also mean a very nonspecific
00:03:04 - reaction of the body to a pathological perturbation?
00:03:08 - I think one way to look at it in a kind of integrated way is to say that everywhere
00:03:14 - and all the time in the body, we need to respond to stressful or noxious or infectious stimuli.
00:03:23 - And that because we are wired to do that, it's possible sometimes that those
00:03:31 - control points will be insufficient or will be overly robust. bust.
00:03:36 - And then that may be the real basis of inflammatory disease,
00:03:40 - or maybe all disease, if all disease has an inflammatory component.
00:03:44 - So in a sense, we can make the argument that it's failure of control that is
00:03:52 - what makes inflammation bad.
00:03:55 - Because within a range, inflammation will stay local.
00:03:59 - And when it stays local, it generally does what it's supposed to do.
00:04:02 - It's possible for it to become overly robust locally to a point,
00:04:08 - but most of the time that is still compatible with reasonable organism health.
00:04:17 - The hypothesis would be that once either the stimulus is too prolonged or too
00:04:22 - big or that there is a genetic variability that makes one over responsive or
00:04:30 - under or in or unable to control sufficiently well.
00:04:34 - Well, now inflammation spills over into the systemic circulation.
00:04:39 - And that's typically when we would say, this is a bad, this is a disease, this is a bad outcome.
00:04:47 - And so then, of course, the corollary to that is that it is the brain and neural
00:04:55 - circuits that are now failing at their job to keep inflammation localized.
00:05:06 - We don't know yet whether this is neural. We don't. Because in some sense,
00:05:10 - we didn't even get to the point that we really defined inflammation.
00:05:15 - What does inflammation actually really mean? Because in some sense,
00:05:18 - it seems to be a phenomenon that is deviating from the standard,
00:05:23 - but it can occur at many different spatial temporal scales and also with varying levels of intensity.
00:05:31 - So how do we now really define inflammation? What's inflammation exactly?
00:05:35 - So at a core level, I keep using the phrase that inflammation is communication.
00:05:42 - So I think inflammation is an intermediate set of pathways that connect the
00:05:48 - original insult or injury or deviation from homeostasis to some response to that, right?
00:05:56 - So of course, the typical control systems you're thinking of are neural control
00:06:00 - and you're thinking of the nervous system as having that function.
00:06:03 - It probably happens on a faster timescale than what inflammation does.
00:06:09 - So inflammation is the communication framework, but now the problem is that
00:06:12 - the language of that communication can itself become the cause of the disease
00:06:18 - or the aspect of the disease that becomes propagated or gets worse or cascades
00:06:23 - further and further out of control.
00:06:25 - So inflammation has this dual role, or you could argue that it's an intrinsic role.
00:06:31 - The very fact that it's an intermediate timescale process and that it uses molecules
00:06:40 - that can cross into, say, the neural system, but also into other aspects of physiology.
00:06:44 - Set it up for this possibility that if things go out of control,
00:06:49 - the very act of communication becomes the detrimental thing.
00:06:55 - And and now you may not even be able to find any
00:06:58 - evidence any remaining evidence of the original stimulus that
00:07:01 - started the whole process the whole dominoes falling
00:07:05 - you just see the dominoes are falling right
00:07:08 - so now and now the problem becomes that it's the dominoes falling
00:07:11 - that are your problem and that's when people say this is an inflammatory disease
00:07:14 - they focus on those mediators um in fact they they often confuse or or or interchange
00:07:21 - the term marker and mediator you So as if a molecule that is there in the body
00:07:29 - is doing nothing more than to act as a marker of something.
00:07:32 - Of course it's not. It's having a biological effect. So it's a mediator.
00:07:36 - If you now bring it down to the simplest form, what's the simplest form of inflammation
00:07:41 - that would still qualify for that label?
00:07:45 - Uh i would argue the simplest form of inflammation
00:07:48 - can be seen in very primitive organisms or even perhaps single cell organisms
00:07:53 - where there's a stress response so the the response to anything like a chemo
00:07:59 - ismotic stress even a lack of nutrients or an overabundance of some some stimulus,
00:08:07 - the molecules and signaling pathways that one can find are sort of a proto-inflammatory
00:08:14 - response because those same molecules are typically implicated in doing something inflammatory.
00:08:21 - If you were to just give those molecules, you will see a response that you could argue is inflammatory.
00:08:26 - We did some of our studies.
00:08:30 - I didn't go to the lowest level organisms,
00:08:33 - but we did some studies on malaria and
00:08:36 - we were looking actually at the mosquito host for the malaria parasite and show
00:08:41 - that that mosquito host is elaborating exactly the same types of responses that
00:08:45 - the human host does right so now this mosquito that is thought of as part of
00:08:50 - the problem in the disease you know for carrying the vector for being the vector for disease.
00:08:56 - You might say, well, it's not harmed in any way, it doesn't care,
00:09:00 - or perhaps it's even benefiting from transmitting this disease.
00:09:02 - But the reality is that it doesn't. It's fighting this disease tooth and nail.
00:09:05 - In fact, the disease would be way worse if it wasn't for the fact that this
00:09:09 - mosquito has done a quite good job of limiting the parasite burden in itself
00:09:13 - before it ever bites the host.
00:09:16 - And as a separate twist, the act of blood feeding,
00:09:21 - depending on the kind of host that it is, if that host is infected,
00:09:26 - There will also be inflammatory meteors that transit into and get internalized
00:09:30 - into the mosquito, and the mosquito recycles them and uses it for its own signal
00:09:34 - transduction to fight off the parasite.
00:09:36 - So there's this entire almost ecosystem-type effect where inflammation is no
00:09:41 - longer about just what happens to the one organism, but it's about a cross-organism
00:09:45 - transfer of information.
00:09:47 - So you would see that's originating already in single-cellular organisms,
00:09:52 - so it's a very old mechanism.
00:09:54 - Yes. So it means they won't understand it. We shouldn't start looking at complex
00:09:57 - multi-organ systems, right?
00:09:59 - You should start with single-cellular ones. People are doing great studies in
00:10:02 - zebrafish, for example, because they're very amenable to perturbation and visualizable
00:10:07 - in terms of fluorescence. Should we start with E.
00:10:08 - Coli or something like single-cellular? So people have,
00:10:13 - I mean, typically what they do is then they engineer the unicellular organism
00:10:19 - to be able to record what essentially it's doing and so forth.
00:10:24 - The problem with that is that that's great if you're trying to come to the kind
00:10:30 - of evolutionary mechanisms and initial set of feedbacks and so forth.
00:10:36 - But because the problem with that approach, though, is that because we can also,
00:10:41 - because we can show that isolated cells from,
00:10:45 - say, people or mice can be put in culture and can exhibit this inflammatory
00:10:50 - response that has many features that we can see at the tissue and the organ and the organism level,
00:10:56 - the problem is that the two things aren't automatically dockable.
00:11:00 - Just because we can see it at the single cell level doesn't mean
00:11:03 - that we automatically understand the way inflammation is
00:11:06 - really really regulated because normally you will never have
00:11:09 - any of our cells just sitting there by itself it's always going
00:11:12 - to be in the environment of the entire organism so you
00:11:15 - know it's a teleologic argument are you you know maybe what you really need
00:11:18 - to understand is the entire organism and and control as a system to infer the
00:11:25 - core features that matter there and see which of those features can still be
00:11:29 - recapitulated at the individual cell But at the bottom,
00:11:33 - would it be fair to say that it is linked to the homeostatic functions of the
00:11:41 - single-celled organism?
00:11:43 - And then maybe we should limit it to the very specific homeostatic functions,
00:11:48 - the Materana and Varela called autopoiesis, which is, it is the homeostatic
00:11:54 - function that allows the self-maintenance of the organism.
00:11:58 - Right? So, it's not just necessarily think every energetic status,
00:12:03 - but it's really about the integrity of the organism itself.
00:12:08 - And as soon as that control loop starts to become perturbed,
00:12:11 - that's when we start to see inflammatory responses.
00:12:14 - Right. Would that be reasonable? Do we link it to autopriasis in that sense?
00:12:18 - Yeah. I think one interesting application of that would be to help define thresholds.
00:12:21 - So like for particular pathways.
00:12:26 - Defining which ones perhaps are the, the original ones or the closest to the
00:12:31 - original ones, what were the original actual functions and seeing whether those
00:12:34 - functions are recapitulated at higher orders of org of organization.
00:12:38 - That I think would be very good. I think being able to, as you said,
00:12:41 - help help define what are the actual, uh,
00:12:45 - what are the actual interactions that, that cross a threshold from being normal
00:12:51 - everyday housekeeping to being something that's now quote inflammatory.
00:12:54 - Inflammatory um i think that would be quite quite
00:12:57 - useful it is very interesting that you talk about metabolism because
00:13:00 - now of course we're appreciating that metabolism and
00:13:05 - inflammation and immunity are highly linked so t-cell functions
00:13:08 - macrophage functions other inflammatory type cell
00:13:11 - functions are very dependent on metabolic
00:13:15 - fluxes and of course end up regulating metabolism right
00:13:18 - so but now if we go from single cell to multi-cell let's say we go to a slime
00:13:23 - mold or something simple would you see that when a slime mold um does it is
00:13:31 - the response of this collection of cells and make a slime mold already qualitatively
00:13:36 - different in case of inflammation.
00:13:38 - Than the single cylinder organism does
00:13:42 - a slime mold start to do different things i i
00:13:45 - think the slime mold starts to do different things because now there's
00:13:49 - an entire additional set of functions that come
00:13:52 - along that need to be optimized as
00:13:55 - as as a as a necessary uh uh
00:13:59 - as a necessary function of that additional cellularity so the there's a cost
00:14:05 - to to to maintaining that additional cellularity there's a greater distance
00:14:10 - uh there's a greater uh there's a greater need to have nuanced timescales of response,
00:14:16 - and now one might imagine that there's additional, of course,
00:14:24 - biological pathways that come
00:14:26 - along with doing that, and so then that system has to be synchronized.
00:14:30 - But yet, if one identifies what one might imagine are the core,
00:14:35 - core functions, those functions still have to be retained, right?
00:14:39 - So now how do you propagate from the single cell to the multi-cell while still
00:14:42 - retaining the overall qualitative behavior, right?
00:14:45 - That I think is where the really interesting insights will probably come along
00:14:49 - because that might actually even speak to.
00:14:55 - How each step of evolution necessitated an additional set of new branches that
00:15:02 - together had to be synchronized to achieve a macroscopic behavior of the entire system. Right.
00:15:10 - Yeah. So if you go now to the multicellular organism, would you see the reaction?
00:15:17 - So for instance, temperature change is a typical expression of an inflammation, right?
00:15:22 - Yes. Is temperature change also something that the single-cell organism would
00:15:26 - display or that the multi-cell organism will display?
00:15:30 - No, I mean, they're going to be dependent on their external environment,
00:15:33 - but they may very well respond differently than they do in terms of the temperature.
00:15:40 - So this whole heat shock response is intimately intertwined with inflammation.
00:15:48 - So heat shock proteins are actually a prototypical category of these damage
00:15:55 - associated molecular pattern molecules or damps as we call them.
00:15:58 - So they are molecules that do various housekeeping functions in their normal context,
00:16:06 - but when present in abnormal context, either in the wrong place or at the wrong
00:16:11 - time or in the wrong context of additional molecules,
00:16:15 - now become sensed as danger or alarm.
00:16:20 - And so, again, another interlinking between the environment,
00:16:27 - sensation of the environment, and adaptation to the environment,
00:16:31 - and inflammation, right?
00:16:32 - So, again, comes back to this thesis or hypothesis that inflammation is communication.
00:16:41 - Communication because at the end of the day, inflammation isn't,
00:16:45 - at some level, inflammation isn't a thing in and of itself normally.
00:16:49 - It's just a way of transmitting the information from a beginning to the end.
00:16:54 - It's just that when it rises above a certain threshold, because it's now intertwined
00:17:00 - with so many other pathways, inflammation now becomes.
00:17:04 - The causative agent or inflammation acquires the
00:17:07 - word inflammation becomes the word inflammation yes information information
00:17:11 - is information yeah you could say
00:17:14 - it's information or you could say it's communication it's sort of similar
00:17:16 - to non-specific because in some sense anything is information if you want right
00:17:21 - right so but not every single thing that's information can can become causative
00:17:26 - for something that that is pathological so yeah but if if if we if we would
00:17:33 - agree with this early definition of autopoiesis,
00:17:36 - self-maintenance of the organism as a system.
00:17:40 - This would require forms of communication between constituent components.
00:17:45 - But in the end, isn't it more a form of actuation to set in motion certain reactions
00:17:53 - at the lowest level, certain biochemical processes,
00:17:57 - to assure maintenance of the system?
00:18:01 - Yes. No, I would imagine that in a lower organism, it's perhaps more actuation
00:18:07 - because you're already a single cell.
00:18:10 - And so you don't really need to communicate. Although perhaps you communicate
00:18:14 - quorum sensing or, you know, in a sense you're communicating to nearby cells, that's possible.
00:18:19 - Communicating a sense that, you know, use your flagella to swim away from this
00:18:26 - and towards that or whatever.
00:18:28 - Ever uh but but yes i think at
00:18:31 - some very basic level it is actuation and then
00:18:34 - you could imagine that as you move up with evolutionary scale that actuation
00:18:37 - becomes subsumed into a set of biochemical pathways where they don't directly
00:18:43 - uh create motor uh actions in any given direction or another but actually transmit
00:18:50 - biochemically the sense that something must be done.
00:18:55 - Yes. So if you say transmitting that something must be done is actuation,
00:18:59 - then I'm perfectly okay with the word actuation.
00:19:02 - This is cool, right? Because now we have a media foundation to look at these
00:19:05 - more complex forms of inflammatory responses that you might find in those organ
00:19:10 - systems and so on, right? Right. So.
00:19:15 - And now you indicated, so because you also want to look really a little bit
00:19:19 - at how, okay, how does this possibly relate to the neural control of inflammatory response?
00:19:25 - And of course, brains start to emerge when, when you have to coordinate across
00:19:31 - multiple parts of, of a system, right.
00:19:34 - That cannot necessarily at a direct signaling level, level exchange information
00:19:40 - because they would not have the signal capacity.
00:19:44 - Right, it's too far apart, right, exactly, yes, yes.
00:19:47 - Or there might be transduction delays that you have to overcome and so on, right?
00:19:51 - So the brain starts to get involved as soon as you have a multi-component system,
00:19:57 - multi-organ system if you want, where you have to coordinate across these systems.
00:20:03 - So, that would suggest that if we talk about the skeletal muscle system,
00:20:09 - or you talk about, or use the muscle system to control if you're a worm,
00:20:14 - or we talk about regulation across the inflammatory responses of subsystems, right? Right.
00:20:21 - So how do you look at that? Do you see it like every subsystem has its own intrinsic
00:20:27 - inflammatory response or there's a perturbation, there will be an automatic reaction,
00:20:31 - predefined, genetically tightly controlled, that then has to be regulated yet
00:20:37 - again by either an immune system or a nervous system, right?
00:20:41 - So how do you see that these three components work together?
00:20:44 - So I think that it's actually sort of both.
00:20:48 - So you have...
00:20:52 - You have the organs, the typical, the typical organ structure,
00:20:56 - let's call it, let's say even at some level of tissue is,
00:21:01 - is the structural or functional cells or parenchymal cells that do the job that
00:21:07 - differentiates this organ from being this other organ, or this tissue from being this other tissue.
00:21:12 - Typically interspersed among them are these resident inflammatory cells like
00:21:16 - macrophages and others.
00:21:18 - And then typically touching on them are nerve termini.
00:21:21 - And so we can observe that the tissue in some sort of isolation will exhibit
00:21:28 - this inflammatory response, but we also exhibit coordination across tissues
00:21:34 - or across organs, right?
00:21:36 - And so for example, in some fields, people talk about the gut as the motor of inflammation, right?
00:21:43 - And of course, the gut has got its own innervation. It has a sort of primitive brain.
00:21:48 - The gut is quite central for many reasons in coordinating responses,
00:21:53 - but the brain is controlling the gut, right?
00:21:56 - So the gut can do its own inflammation.
00:21:59 - The liver can do its own inflammation. A lung can do its own inflammation,
00:22:03 - which makes sense, especially the lung, for example.
00:22:05 - You're breathing in particulates, though some of those may also be pathogens
00:22:08 - that you're breathing in.
00:22:09 - You have to to be able to deal with them locally and presumably
00:22:12 - you have to send information that you're dealing with them locally to the
00:22:16 - brain and then the brain kind of keeps tabs on this and and says okay are you
00:22:20 - is is the branch office doing a good enough job of dealing with this or do we
00:22:23 - need to involve the head office but it's not that you wait necessarily i would
00:22:28 - think until the problem is out of hand at the branch office you're you're sort
00:22:32 - of keeping tabs right then at some point.
00:22:36 - That is also the the act of
00:22:39 - keeping tabs at the brain level presumably is also
00:22:43 - activating pathways in other organs for whatever appropriate reason either for
00:22:48 - a need to further ramp up or because for example a pathogen can can can evolutionarily
00:22:53 - have been anticipated to move from one organ to another through the blood or
00:22:57 - through the nervous system right so the threat is this dynamic is is evolving dynamically.
00:23:02 - And so then the system is kind of doing its best guess at how to evolve dynamically, right?
00:23:06 - And as long as it's all under control, the threat or the damage is dealt with
00:23:12 - in some fashion, it's contained.
00:23:13 - And then there's an element of having already from the beginning started some
00:23:19 - anti-inflammatory, meaning stopping functions.
00:23:22 - And also these same functions are pro-healing. And so you're beginning the healing cascade as you go.
00:23:26 - If it all works out great, uh everybody at the
00:23:29 - brain level kind of uh congratulates themselves that
00:23:32 - the the crisis was main was was addressed um and then some amount of time later
00:23:38 - the tissues return to some sort of homeostatic uh state that's compatible with
00:23:42 - life as a as a as a system but the problem becomes i think when either the thread
00:23:48 - is too large the it moves too fast um.
00:23:52 - Persists for too long, or because of the other evolutionary trade-off,
00:23:57 - which is genetic variability that we have to have.
00:24:00 - You have a particular organism whose genetic variability makes him or her that
00:24:06 - much more prone to respond.
00:24:10 - I think more prone to respond to assess damage and think I have too much damage
00:24:15 - or more damage than I actually have, or I have more stress than I actually have.
00:24:19 - That's often tied to pain, right? Pain is very subjective.
00:24:24 - There isn't any clear molecular correlate of pain. It's something that you have
00:24:27 - to kind of assess subjectively.
00:24:28 - And coincidentally, of course, that is a very much a nervous system phenomenon.
00:24:32 - So it's very possible that an organism is at a genetic level,
00:24:38 - somewhat overly sensitive or potentially the other way around,
00:24:41 - not sensitive enough, right?
00:24:43 - But you need that range in the population to just evolve.
00:24:47 - So which means that that individual will now become sick.
00:24:51 - That inflammatory response will progress further than it ought to.
00:24:57 - And now that can lead to all kinds of detrimental consequences.
00:25:01 - You would imagine at the farthest end, evolutionarily speaking,
00:25:04 - that if it's incompatible with life, the damage is too much,
00:25:07 - this organism dies, those genes presumably are not passed on,
00:25:12 - an editing process has occurred.
00:25:13 - So inflammation even subserves that role.
00:25:17 - We moved a bit fast now. So if you take the example of the lung, right?
00:25:20 - So okay, I have particulate matter and then there's the lung,
00:25:23 - it triggers an inflammatory response.
00:25:27 - Now, who wants to know about that for what reason, right?
00:25:31 - If we take this sort of more anthropomorphic perspective, before even the brain
00:25:37 - starts to worry about this, which other organ would even care, right?
00:25:41 - The heart might care because, okay, lung capacity is going down. So I got to pump harder.
00:25:46 - So I want to know about this as an example. Yes.
00:25:49 - So, so in that sense, in terms of, if we take, get this, this,
00:25:53 - this, this perspective of maintaining the integrity of the organism.
00:25:57 - Who wants to know about any kind of perturbations at the level of the lung?
00:26:02 - Well, at some level, if you're in an environment where you're breathing in toxic
00:26:06 - materials, you might need to actuate functions that, you know,
00:26:10 - that activate a program to move you away from that environment, right?
00:26:14 - A kind of survival program. This is a noxious environment.
00:26:17 - I need to move. Those functions are already there, right? At some level,
00:26:20 - the brain is already doing that.
00:26:21 - But maybe that's not for such a rapid and massive change that says,
00:26:26 - you know, I'm I'm living in, all of a sudden I've been put into a very low oxygen
00:26:30 - or a very high CO2 environment and I need to propel myself out of there.
00:26:33 - I may be in something that's a more slowly evolving threat on that timescale.
00:26:38 - I'm only finding out about it three hours later, right? And so then maybe that
00:26:42 - triggers a sensation that you need to get out of there and go somewhere else.
00:26:48 - But yeah, of course, other organs in the meantime are also going
00:26:51 - to need to be responding to adjust their physiology appropriately to this new
00:26:54 - load you you cannot do what you were doing before because you're also dealing
00:26:59 - with this additional uh particular or pathogenic burden or some other type of
00:27:04 - damage i now need to compensate around that uh a key one one one obvious one is in.
00:27:10 - Following injury you will have you may have severe bleeding um a key inflammatory
00:27:16 - mediator interleukin-6 activates the coagulation cascade.
00:27:21 - So you're rapidly activating a coagulation cascade to close up that hole.
00:27:27 - Of course, the problem is that
00:27:29 - the coagulation cascade now feeds back and activates more inflammation.
00:27:33 - Because, I don't know if because, but at least you can speculate that if you
00:27:38 - have a big hole in your body, the next thing that's coming is a massive wave
00:27:41 - of bacteria from your own skin or from the environment or whatever.
00:27:44 - So there's going to be an invasive an invasive pathogenic opportunity there from that hole, right?
00:27:48 - It's not that the body is sensing the hole necessarily, but it's sensing that
00:27:53 - there's a blood loss, which must be due to a hole, right?
00:27:56 - So now you're activating a pathway of coagulation, and perhaps it's disseminated,
00:28:03 - which happens in multiple places.
00:28:05 - Perhaps because, again, it's preemptively coagulating because bacteria will
00:28:10 - probably be entering and so they'll get to various places.
00:28:12 - And so now you need to coagulate to create barriers to trap these bacteria.
00:28:16 - That coagulation is pro-inflammatory, again, because you need to wind yourself
00:28:22 - up for the eventuality that you might have a pathogenic fight on top of your
00:28:27 - traumatic injury fight.
00:28:29 - If all of that gets spun up too much out of control because there's an inherent,
00:28:33 - very strong positive feedback, you could imagine in a setting that's not supported
00:28:37 - by modern medicine, that's now no longer compatible with life.
00:28:41 - And so then the organism will die. And even that's good because the organism's
00:28:45 - death means that that organism is not transmitting the pathogenic agent to the rest of the population.
00:28:51 - And if it's a trauma and not with a pathogenic population.
00:28:55 - Well, that organism is not bringing the predator back to the rest of the population,
00:28:59 - right so even at an evolutionary level
00:29:03 - you could imagine that this is actually something that's that's beneficial
00:29:07 - evolutionary but it means for these multi-organ uh systems
00:29:10 - there are predefined response patterns
00:29:13 - as you now describe them yes so how big is that
00:29:16 - repertoire you think so you're talking about the that that the organ specific
00:29:20 - response pattern so yeah we we've we've addressed address some of that by trying
00:29:24 - to look at a defined panel of inflammatory mediators that interrogates a broad
00:29:31 - array of inflammatory and immune pathways that are known to sort of be interlinked.
00:29:35 - And when you do that, and you do that in response to a sort of a prototypical stimulus,
00:29:40 - which is sort of one molecule derived from bacteria that is a known potent amino stimulant,
00:29:46 - so you're using that as a sort of prototypical system that you
00:29:49 - can control and you can uh you can
00:29:52 - actuate quantitatively um you do
00:29:56 - find uh quite different dynamic
00:29:59 - responses in an organ specific fashion um you
00:30:03 - can kind of on depending on the tools you use you can uh quantify peaks and
00:30:08 - valleys in this dynamic process and begin to think that you that there is a
00:30:13 - sort of programmed temporal wave or spatio-temporal wave of this inflammatory response.
00:30:21 - And that it is
00:30:24 - presumably happening that way
00:30:27 - for some evolutionarily conserved
00:30:31 - reason that relates to the
00:30:34 - likelihood that that specific pathogen is what you've
00:30:37 - got and the pathways by
00:30:40 - which that pathogen may disseminate or the locations to which that pathogen
00:30:44 - may go and cause very serious harm versus not so serious harm are those ones
00:30:49 - that are responding sooner versus later and so forth of course those are all
00:30:53 - hypotheses to be tested at something but the way you describe it now sounds like um.
00:31:00 - A large chunk of of the inflammatory response
00:31:03 - is relying on these
00:31:06 - predefined response patterns at the organ level i
00:31:10 - i think so i mean because because it at some level the organ is a compendium
00:31:15 - of its cells right even if we took out the potential for neural control now
00:31:19 - okay because the alternative hypo or the related not necessarily alternative
00:31:23 - hypothesis is that the reason or that we see these organ-specific patterns is
00:31:27 - because of the way neural control works.
00:31:30 - Which regions of the brain activate first, second, third, and where do they
00:31:34 - project, and where does that response happen?
00:31:37 - At some level, I think it's a semantic argument. My guess is evolution would
00:31:40 - not have gone that way if it wasn't beneficial to activate inflammation in a
00:31:45 - particular sequence, I would guess.
00:31:48 - But at some level, an organ is a compendium of the cells that it has.
00:31:53 - Some organs have a a greater proportion of sort of their parenchymal cells relative
00:31:58 - to their resident inflammatory cells than other organs.
00:32:03 - A prototypical organ is, again, the intestine, the gut.
00:32:06 - Of course, we all know the gut is really the outside of the body at some level,
00:32:11 - right? So you, of course, in the lung is another one.
00:32:13 - So these are surfaces that are directly, essentially in contact with the outside world.
00:32:18 - It's not illogical to assume that these are ones that need to be very finely
00:32:23 - tuned in terms of how they regulate their inflammatory response because you
00:32:27 - are constantly impacted by the outside world,
00:32:30 - you can't have a situation where you're constantly inflaming out of control
00:32:34 - and having all of your organs kick in for any stimulus that comes along.
00:32:40 - There have to be very high thresholds that have to be exceeded in order to really
00:32:47 - get the cascade flowing downstream.
00:32:50 - There's other organs that are obviously more internal that if they come into
00:32:55 - contact with a bacterial-derived immunostimulant molecule.
00:33:00 - The interpretation must be there's bacteria already inside, right?
00:33:04 - They're already present. They already have made it through the barriers.
00:33:07 - So activate right away, right? You could imagine that that would be the program.
00:33:12 - And there's some seminal papers about gut inflammation, the ones that define
00:33:16 - some of the prototypical actions and regulation of the key signaling pathways
00:33:22 - for inflammation like NF-kappa B that show that the gut is sort of wired like that.
00:33:27 - It's pretty much stepping on the brake pedal until a fairly high threshold is
00:33:32 - exceeded, and then the foot is lifted off the brake pedal, and that creates motion.
00:33:36 - Now there's a response.
00:33:38 - Other organs have got the foot much more lightly on the brake pedal.
00:33:42 - Now what you call the inflammatory response, if I compare the inflammatory response
00:33:47 - in the lung, how is that different from the inflammatory response in the liver
00:33:51 - or the spleen or the heart?
00:33:55 - I mean, the molecules that evolve, they might evolve at different times depending
00:34:03 - on thresholds, but they're often very similar.
00:34:06 - There are some molecules that are more present in certain tissues than others.
00:34:10 - Um often when people say inflammatory
00:34:13 - response they sort of are mixing the terms and and are
00:34:16 - talking about not just with inflammation and meaning the
00:34:19 - the direct molecular actions being driven by
00:34:22 - the direct molecules that we can say are inflammatory but then sort of the secondary
00:34:26 - phenomena so for example edema you know so in the lung you will have lung edema
00:34:30 - you might not have it quite as much in say the liver or something like that
00:34:34 - um so or the gut right so it just depends on the, on the, on the, the,
00:34:41 - the, the secondary function that, that, or dysfunction that becomes triggered
00:34:45 - is often also very organ specific.
00:34:48 - But I think that the, the actual mediators that one finds are often a fairly
00:34:53 - well-ordered cascade of, of, of mediators.
00:34:56 - Um, they're typically the earliest responses, let's say to a tissue injury in
00:35:01 - that particular organ are going to be these damps,
00:35:04 - After that is a class of these cytokines that we call chemokines.
00:35:07 - They typically are there to help attract circulating inflammatory cells to the
00:35:13 - local area, but they actually have many other functions.
00:35:16 - And then the classical cytokines, right?
00:35:19 - The problem is it's not like the first thing, then you wait a while,
00:35:22 - then the second thing, and then you wait a while, and the third thing.
00:35:24 - These networks organize very fast.
00:35:26 - And then the next behavior that is very interesting is that they organize very fast across multiple
00:35:32 - tissues where you begin to think that
00:35:34 - the only way that could happen is if there was neural control right because
00:35:37 - how else do you how else can you explain a situation
00:35:40 - where a leg is broken severely and already the gut is beginning to have a problem
00:35:45 - right it's beginning to change its inflammatory profile and then let's say the
00:35:49 - liver and then the lung uh these distal responses that are sensed almost immediately
00:35:54 - right that cannot happen just through simple diffusion Yeah.
00:35:58 - So you introduced this model by Namas and others where they actually distinguished
00:36:04 - sort of three profiles of the inflammatory response, right?
00:36:08 - Where you were talking about, let's say, an etiquette response where you remain
00:36:11 - within the range, which is still supporting the integrity of the organism,
00:36:16 - but there you were making the point it never returns to the baseline. You always change.
00:36:21 - Yes. So you're always not just change, you're typically worse off.
00:36:25 - So, you're leaving behind traces of inflammation.
00:36:29 - You're not simply completely resolving and coming down to baseline.
00:36:33 - So, the additive is also... And which means that the next time that you get
00:36:36 - hit with a stimulus, you're already being hit not at a baseline of zero,
00:36:41 - but at a baseline of plus one.
00:36:43 - And that is why preconditioning, studying preconditioning, and mathematically
00:36:48 - modeling preconditioning have been activities that we've been very interested
00:36:51 - in since the beginning of this process. because, of course, you're never naive.
00:36:54 - You've never been exposed to only one thing.
00:36:56 - By definition, you've already been exposed to a bunch of things by the time
00:36:59 - you're exposed to whatever it is that you're studying, whether experimentally or clinically.
00:37:02 - So to those who mean from a clinical perspective...
00:37:06 - The inflammatory response of every individual patient is uniquely different
00:37:11 - because they are at a different set point. Exactly.
00:37:14 - It's all the prototypical complex system. Initial conditions are perhaps the
00:37:18 - biggest single determinant.
00:37:19 - Okay. And then you also mentioned that the DART can have an excessive response
00:37:24 - that exceeds some threshold, right?
00:37:26 - Or you can have, let's say, a hypoinflammatory response that is sort of more reduced than expected.
00:37:34 - Right. And in both cases, you're outside of this envelope that would sustain
00:37:38 - the organism, right? So why is that significant?
00:37:41 - So in both instances, things should be really strongly supported by empirical evidence?
00:37:45 - Yeah, so we have in one sort of clinical system where we think we can get,
00:37:57 - where we've made many of these insights,
00:37:59 - which is severe traumatic injury.
00:38:01 - In a large population study observational
00:38:05 - study where you know in approximately 500 patients where
00:38:08 - we could first of all interrogate a broad
00:38:10 - array of injury severity so it wasn't just focusing on the most severely injured
00:38:14 - patient it was really a survey across injury severities which was very important
00:38:17 - because you could see the entire envelope of responses and over a pretty long
00:38:22 - period of time we could find sub cohorts of these patients that exhibit these
00:38:28 - phenomena now i mean I mean,
00:38:29 - the original picture that you described was a hypothesis.
00:38:35 - It was, yeah, it was derived from, let's say, clinical experience and maybe
00:38:41 - experimental experience where there's a sense that this is what happens.
00:38:45 - But with being able to actually measure the mediators, create dynamic network
00:38:51 - representations of those mediators, we can, in fact, point to cohorts of patients
00:38:57 - and circumstances under which we see each piece.
00:39:00 - So for example, if you compare highly matched patients that went on to live
00:39:04 - versus went on to die, sort of
00:39:06 - the biggest bifurcation you can have in anything, but of course in trauma,
00:39:09 - you can see the sense of self-sustaining inflammation with networks,
00:39:16 - complexity that rises and rises from pretty much as soon as you can,
00:39:20 - excuse me, as soon as you can measure versus other networks that look sort of
00:39:24 - flatlined and just not responsive at all.
00:39:27 - That's one case. We have patients that have a phenotype of coagulopathy,
00:39:32 - so they're just not coagulating appropriately, or then later on they're over-coagulating.
00:39:36 - And when you look at them, they also, compared to highly matched controls that
00:39:41 - don't have that phenomenon, look like they have just an insufficient inflammatory response.
00:39:47 - And then if you, again, to bring it back to the brain, when we compare.
00:39:52 - The networks of patients that have a spinal cord injury versus highly matched
00:39:58 - patients with similar injury characteristics, but that don't have that spinal cord injury,
00:40:05 - we now again see this hypoinflammation.
00:40:07 - So there's clearly situations that, whether they're all related to each other.
00:40:15 - I mean, for example, the one inference would be that if the spinal cord transection
00:40:21 - gives gives you this profound hypoinflammation.
00:40:24 - Is that relevant for anybody that doesn't have spinal cord transection?
00:40:28 - Does that, I mean, or does it mean that those patients have some degree of neural dysfunction, right?
00:40:34 - Our hypothesis is that we're looking at patients, when we see patients that
00:40:38 - have this hypoinflammation, that they have some degree of neural dysfunction.
00:40:42 - Now, what type of neural dysfunction, I don't know, but we can potentially suggest
00:40:45 - some biomarkers, inflammatory biomarkers that appear to be hallmarks of that.
00:40:50 - Likewise, in the case of But the overly revved up, overly stimulated,
00:40:54 - over-exuberant inflammatory response, again, we can have biomarkers that go
00:40:58 - along with that, and they're different.
00:41:00 - So, yeah, the suggestion is that different programs have been set in motion.
00:41:05 - And the hypothesis for the spinal cord lesion case is that as soon as you detect
00:41:10 - that the blood-brain barrier is compromised.
00:41:12 - You actually want to reduce the inflammatory response to prevent any from these
00:41:17 - signaling molecules actually enter the nervous system.
00:41:20 - Because that's a that's a terrific hypothesis that will be
00:41:22 - huge right because then information hits your nervous system and
00:41:26 - that might be the end of a lot of things so the whole concept
00:41:29 - of a kind of uh hibernation or stasis um that that is the as a as a protective
00:41:36 - mechanism um and i think is absolutely key and i think there's many links to
00:41:42 - inflammation being playing a big role in and communicating that and mediating that. Yeah, so I agree.
00:41:49 - That's a terrific idea. Okay, so now we have the sort of three ranges of responses
00:41:56 - to inflammation, which clearly points to this being a control issue.
00:42:00 - This is a controlled response, but the control can be sort of showing too much
00:42:06 - positive or negative feedback. That's right.
00:42:08 - And also you mentioned in your talk that you see this
00:42:11 - inflammatory response very much as an interaction between
00:42:14 - positive to her negative feedback loops yes i mean obviously that's
00:42:17 - a fairly straightforward way to look at any complex system
00:42:20 - uh but we've developed a set
00:42:24 - of sort of let's call them proto-interactions if
00:42:28 - you want to think about the the functions that might have been there at the
00:42:30 - earliest at the earliest stage of evolution that we can um that we can play
00:42:37 - forward we can we can encode them into mathematical models and we can reproduce
00:42:41 - a range of both qualitative and then quantitative behaviors.
00:42:46 - If we code that set of interactions with that key.
00:42:52 - That key tug of war between
00:42:55 - positive versus negative feedback into agent-based
00:42:58 - models that are say spatially realistic we can
00:43:01 - reproduce patterns that we see in real in real human
00:43:04 - microscopic sort of histology or even macroscopic lesions and so that doesn't
00:43:11 - automatically prove that we're right but we've been we've been able to make
00:43:15 - those leaps because we base them on that that core set of hypotheses of these specific.
00:43:22 - Positive versus negative feedbacks. Yes.
00:43:25 - But I think there are two really interesting consequences of that,
00:43:28 - right? Because you were saying, well, it's not just sequential.
00:43:31 - At first, I'm ramping something up, and then I'm ramping it down.
00:43:35 - Yes. It's very much that positive and negative feedback are operating in parallel.
00:43:39 - In parallel. That seems to be the case. I think this is rather an important
00:43:42 - insight, but the question would be, of course, what's the advantage of that?
00:43:46 - Why would you do it that way?
00:43:48 - Yeah, so it's been very interesting to think about why it is that such a system
00:43:55 - would have evolved that way.
00:43:57 - You could imagine that that's a way to give you much more fine-grained control,
00:44:02 - more rapid control, more nuanced control.
00:44:07 - I also think that at some level, the body or the organism has to sort of,
00:44:14 - its baseline state has to be somewhat anti-inflammatory because of the fact
00:44:18 - that so many perturbations will be pro-inflammatory.
00:44:22 - So the baseline state is not zero, but it's actually trending towards anti-inflammation.
00:44:28 - So for example, let's take something simple.
00:44:33 - Muscle stretching as a function of just daily activity, walking within a range,
00:44:38 - nothing severe, nothing athletic, nothing stress response, fight or flight.
00:44:42 - You're just walking, dealing with normal activity.
00:44:45 - We did some
00:44:49 - work in collaboration with with with other investigators that
00:44:52 - you can you can replicate that as cyclic stress and
00:44:55 - cyclic stretch in a in a cell culture system and what you're seeing is an elaboration
00:45:00 - a tonic elaboration of key uh sort of anti-inflammatory pro-healing mediators
00:45:04 - now simulate a much more dynamic process exercise uh uh sort of fight or flight need to run.
00:45:13 - Now you're stretching faster or bigger sort of amplitudes.
00:45:17 - That entire regime switches over to activation of pro-inflammatory pathways. So-
00:45:23 - So the point is that the system will never know when it needs to switch from
00:45:29 - being just doing its normal amount of movement, if you will,
00:45:34 - to the needing to instantly need to run.
00:45:36 - And you can't trade off evolutionarily. You can't be always inflamed on the
00:45:42 - off chance that you might need to become more inflamed.
00:45:44 - And so then you need to basically have this available bifurcation at almost
00:45:49 - every time step. And every time step, you need to be able to choose to go to
00:45:53 - the right or to the left, to go to pro or to go to anti.
00:45:56 - But not inflamed would mean at the level of the tissue, we need a zero expression
00:46:01 - of any of the markers of inflammation or just a low expression of these markers?
00:46:06 - I think that we get a tonic expression of key anti-inflammatory mediators.
00:46:13 - I think sometimes we can find what look
00:46:17 - like baseline levels of pro-inflammatory mediators but
00:46:21 - they often are there because they're also subsuming other
00:46:24 - physiologic functions or the experimental
00:46:27 - situation we cannot ever truly demonstrate
00:46:31 - that we didn't create some stress in the process of
00:46:34 - creating the experiment to look so there's always that kind of heisenberg uncertainty
00:46:38 - you know the fact that we're observing it is creating the situation that we're
00:46:41 - observing so but in terms of the negative feedback is a negative feedback an
00:46:46 - expression of anti-inflammatory mediators or a suppression of the inflammatory mediators or both.
00:46:53 - Yeah. So this is a big argument in the field right now. And I don't know if
00:46:56 - some of it is semantic or if it actually is a specific thing.
00:47:00 - People talk about resolution, inflammation resolution. You will see this word
00:47:04 - coming up in many papers. And these are very good, very respected investigators.
00:47:08 - There clearly are entire programs whose job it is to resolve inflammation after the fact.
00:47:15 - I think that those are related but
00:47:17 - distinct I think there are two levels there is the
00:47:20 - level of control and decision making some of
00:47:24 - which can stretch out to a longer period of time and then some
00:47:27 - of these same mediators can drive secondary functions that are pro-healing and
00:47:31 - then there's the actual longer term process so it's a well-known feature of
00:47:35 - wound healing that you can sort of shut off that initial inflammatory phase
00:47:40 - and you can even begin to heal a tissue over the next longer time scale,
00:47:46 - but to truly remodel all the way back to something like what you were before
00:47:50 - the injury takes a very long time.
00:47:52 - So you, you, but you were able to kind of, you know, put a bandaid on the problem
00:47:58 - and it just takes a while for the problem to fully, you know,
00:48:01 - at least achieve enough of a scar or whatever to, uh, to further shore up that repair.
00:48:07 - Um, there are many aspects of,
00:48:10 - of, of healing after injury that don't have that skin wound healing kind of
00:48:14 - vocabulary, but it's that same basic idea that you need to, you need to kind
00:48:19 - of shore up the, the, the, the, the, the, the, the, the, the,
00:48:22 - the, the, the, the, the, the.
00:48:23 - Broken or disturbed tissue so that it can go back to doing at least some aspect
00:48:29 - of its job and probably to turn off signaling that tells other organs that there's a problem.
00:48:35 - So you kind of quiet that whole thing down. And then once that's done,
00:48:38 - you can give some time for the resolution processes to really just do their job.
00:48:43 - I think that when you're looking at chronic inflammatory settings,
00:48:46 - which as I mentioned in my talk, I think is more like a chronic restarting of acute inflammation.
00:48:52 - Now you can see these active resolution processes, but that's just a function of the dynamics.
00:48:56 - Because you're constantly restarting, you're never fully healing,
00:49:00 - then you're seeing a resolution program that needs to kick in and stay on for a long period of time.
00:49:06 - And then you can call that now a resolution program because it's tied to the
00:49:09 - resolution of inflammation.
00:49:11 - But if your explanation of chronic inflammation as the result of starting up
00:49:18 - the process of acute inflammation, but is doing it repetitively.
00:49:21 - That would suggest that some timescale you should see transients in the chronic responses.
00:49:27 - Is that the case? I think it is now that people are looking.
00:49:29 - I think that often there is an inherent sort of, let's call it bias.
00:49:37 - You make a hypothesis, and the hypothesis is geared towards,
00:49:41 - let's say, looking at arms of the response that are downstream.
00:49:43 - Well, then, of course, you're going to be seeing the arms of the response that are downstream.
00:49:47 - This is why systems approaches like the ones we do are, I think, very necessary.
00:49:51 - So because we interrogate for the, we stay agnostic and we interrogate the entire
00:49:56 - process all the time at every time point that we study,
00:50:00 - we have a chance, an opportunity to actually see mechanisms that are acute being
00:50:08 - turned on. We also see the reverse phenomenon.
00:50:11 - We see a very rapid activation of processes that are thought to be more chronic.
00:50:15 - But again, they're in the context of also processes that are very acute,
00:50:19 - which I think is just a part of the hallmark.
00:50:21 - Yeah. And I mean, the building of dynamic networks or network representations,
00:50:24 - of these are also key because people tend to focus on single mediators.
00:50:28 - So you measure 30 mediators and you say, okay, I'm seeing a program.
00:50:31 - But of course, in order to say that you're seeing it, it has to pass a statistical
00:50:35 - test and if it doesn't pass the statistical test then you're not seeing it.
00:50:38 - But if you look at it out of the network, you all of a sudden find that it's there. Right.
00:50:42 - But also, if you look at these interactions in the positive and negative feedback
00:50:46 - loops, they are used and then distinguish establish a predefined component and
00:50:52 - a more adaptive component.
00:50:53 - Yes. So who's the mediator of the adaptive component?
00:50:58 - So the adaptive components are, I'm assuming that you're meaning the cells and
00:51:04 - the mediators that are characteristic of the adaptive immune response?
00:51:08 - Yeah, like T-cell mediator responses that you mentioned.
00:51:10 - Right. So some of the mediators are shared.
00:51:14 - So T-helper type 1 or T-helper type 2 are now, you know, Th17,
00:51:19 - and there's many other subsets that have evolved, but let's just for simplicity's
00:51:23 - sake, focus on the Th1 versus Th2.
00:51:26 - There's a set of mediators that are also being made by innate immune cells,
00:51:32 - but that happen to serve the program of driving the differentiation of, let's say.
00:51:41 - Specific subsets of T cells that have fairly specific T cell receptors that say,
00:51:46 - for example, might be specific for the particular pathogen you got infected
00:51:49 - with because it is efficient in the face of a long-lasting infection,
00:51:57 - to focus on just that infection rather than a generalized alarm that
00:52:00 - impacts many bystander cells
00:52:03 - and many other systems negatively right the initial
00:52:06 - the initial responses is fairly non-specific and there's a trade-off which is
00:52:11 - you're damaging your cells the trade-off on the one hand is a necessary price
00:52:16 - to pay but on the other hand it's part of the amplification loop because the
00:52:20 - damage that you're doing to the cells produces these damps which further amplifies
00:52:23 - and And so it's part of the structure. It's actually not just bystander damage.
00:52:26 - It is bystander damage, but it's
00:52:28 - also bystander damage that is part of the structure of the system, right?
00:52:37 - So that's okay within a range, but now after a certain point,
00:52:40 - you can't tolerate that anymore.
00:52:41 - The signaling aspect of the damage becomes secondary to the actual damage part of the damage.
00:52:47 - And so then you don't want to keep, You can't keep that going non-stop.
00:52:54 - It has to sort of segue to something else.
00:52:57 - So the system is already building up the potential to become focused,
00:53:01 - but you don't want to become focused too soon because that isn't intelligent.
00:53:04 - It's the equivalent of what happens in the vaccine setting. We vaccinate for
00:53:07 - flu. It's the wrong strain.
00:53:10 - And now we have no protection, right? We force the system to go in a certain direction.
00:53:15 - Infection a vaccine is nothing more than an
00:53:18 - adjuvant which activates the innate immune response and the antigen
00:53:22 - part which activates the adaptive part but that the
00:53:25 - system is a cascade working together so we force it to go in one
00:53:27 - direction with the vaccine but maybe we forced it in the wrong direction so
00:53:31 - now we have too much of a response for exactly the wrong thing and now the vaccine
00:53:35 - is not functional um in the but the thought is that it's still better than trying
00:53:40 - to do it by random coincidence and just activating the pre-existing clones that
00:53:44 - you have for that specific infection.
00:53:45 - But absent modern medicine, that's how you'd have to do it. You would have to.
00:53:51 - As soon as possible, but not too soon, segue over to a response that's as focused
00:53:56 - as possible to the actual problem that you have.
00:53:58 - Right. So, does that then also explain or at least suggest why at some point
00:54:06 - just bringing the brain as a control system?
00:54:08 - As I said, I think that the brain is an almost necessary control mechanism once
00:54:17 - you achieve a certain structure, a certain compartmentalization, a certain size.
00:54:23 - As soon as you have to optimize more than one function, it's not just get me
00:54:28 - away from this gradient or push me towards that other gradient or fight off
00:54:32 - that one bacterium. I now have to have many systems that need to be optimized.
00:54:35 - I need to trade off over a period of time. Maybe I'll trade off some liver function
00:54:39 - because the liver is very resilient.
00:54:42 - I might trade off some lung function, but, you know, how much,
00:54:45 - how much, you know, I could trade off some gut function, you know,
00:54:49 - but how much heart function am I willing to trade off? Right.
00:54:52 - And so on. I mean, and yet, and they all do. There's phenomena
00:54:56 - that happen in every one of those organs that involve things like
00:54:59 - stunning and hibernation where pathways are being turned
00:55:02 - off to to to limit damage to retain energy
00:55:05 - the system is is doing a lot of of
00:55:08 - adjustments to this right uh and
00:55:12 - my sense is that that would not be possible without uh the brain but it's also
00:55:18 - clearly possible at some level without the brain right so that the tissue is
00:55:22 - able to do it but then to do it truly in a coordinated fashion you need the
00:55:24 - brain You could do it with predefined rules,
00:55:28 - I could claim, as long as the system doesn't show histories and memory.
00:55:34 - But if every challenge to the system leaves a trace in memory,
00:55:38 - then your predefined rules by necessity have to fail because they can never
00:55:43 - take into account all these varying set points, right?
00:55:46 - So maybe this is the main reason why you would need a brain,
00:55:49 - but that would suggest then that your brain has to have a representation of
00:55:55 - these set points, of these changing set points.
00:55:57 - So is there any data that would support that?
00:56:02 - Yeah, I think it does. I mean, in fact, just even observing the system and measuring
00:56:08 - key mediators, you can actually see a sense of this early hysteresis,
00:56:15 - which settles into a trajectory.
00:56:16 - In fact, we've got a study on this coming out very soon, hopefully,
00:56:21 - I mean, submitting it soon, that actually discovers in trauma patients or using trauma patients,
00:56:28 - but something that we find in other systems as well a regulatory architecture
00:56:31 - that we infer from having collected the data over
00:56:34 - time and modeled it as a network um and then
00:56:37 - encoded that hypothesis into a sort of a boolean model and and then playing
00:56:43 - it forward and she's seeing that many qualitative and quantitative features
00:56:47 - of the system become reproduced from this and it's a network that's bouncing
00:56:50 - 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 - of course, driven by the starting points of the system, which are individual specific.
00:56:59 - So people come into this with different initial set points.
00:57:03 - But if you run this simulation across time, you will see an early hysteresis,
00:57:07 - and then it settles on a trajectory.
00:57:09 - And you can map that to, I think you can map that to what might be happening
00:57:16 - in different organs and how the system responds as a whole. Right.
00:57:22 - But now the brain control, how does the brain represent that system that is prone to get inflamed?
00:57:34 - What's the resolution of it? So it seems like at least two key inflammatory
00:57:42 - mediators that happen to also be ones that drive this positive feedback loop
00:57:46 - are expressed in the brain in settings where inflammation is happening at a peripheral organ.
00:57:54 - Either peripheral, like a peripheral organ alone, where you can give the noxious
00:57:58 - stimulus directly into that organ, and you can induce an inflammatory response
00:58:02 - that is not just spilling over systemically internally.
00:58:06 - But is staying fairly localized, the brain in the area that also happens to
00:58:10 - control the function, a key function of, let's say, that organ,
00:58:14 - in this case, the lung, is expressing this inflammatory meter.
00:58:20 - It's present in the lung. It's present in the brain.
00:58:22 - It's not just present everywhere. So it's not a giant diffusion issue.
00:58:25 - And the region of the brain also
00:58:28 - happens to be the one that regulates a particular function of that organ.
00:58:32 - And you can measure that that function becomes disturbed. Dr.
00:58:35 - That's the nucleus tract desolator. Yes, the nucleus tract desolator.
00:58:38 - Dr. But do you imagine, as we have a somatosensory map of, let's say,
00:58:43 - the things we touch or in the properties of our muscles,
00:58:46 - you would imagine that I have a similar map representing all my organs and their
00:58:51 - inflammatory state? Right.
00:58:53 - One could imagine even interesting, one could take a little flight of fancy
00:58:58 - and say say, things like acupuncture or acupressure that are based on the concept
00:59:06 - of meridians are doing that.
00:59:08 - It's a manual way of creating that same thing. You create pressure at a distal
00:59:12 - location, which sends a signal to the brain, which can impact the liver, right?
00:59:17 - In martial arts, you have the ability to potentially strike a particular location
00:59:22 - in a peripheral area and have that translate to damage to the liver or the heart.
00:59:27 - So intuitively or empirically, people over the years have figured out that you
00:59:34 - can actually even use these methods for good or for bad.
00:59:37 - And so I think that is in fact how the system is wired.
00:59:41 - The system is wired so that there is a sensation of damage or dysfunction in a particular location.
00:59:51 - There's an impact there's a sensation of that in the brain in a particular area
00:59:56 - and then presumably if that's above a certain threshold there's a secondary
01:00:00 - activation of inflammation in the peripheral organ.
01:00:04 - One would like to believe that within a range, this is something that's evolutionarily
01:00:07 - beneficial for some reason.
01:00:08 - As I said, either that's because it's doing it in anticipation of there being
01:00:14 - a dysfunction that's going to
01:00:15 - occur in that organ or an infection that's going to occur in that organ.
01:00:19 - And so there's a pre-positioning of defenses or even a pre-starting of a healing program.
01:00:25 - But also just be an artifact, right? Or it could be an artifact.
01:00:28 - You have multiple somatosensory maps.
01:00:30 - Yes. And maybe, let's say, delivering one map ends up to the lower arm in another map.
01:00:35 - But in the brain, there goes so much activity, it can spill over.
01:00:40 - I could totally see that happening as well. And so then maybe that's when it
01:00:44 - becomes pathological, because now you're getting triggering for completely stochastic
01:00:50 - reasons or just reasons that have to do with proximity.
01:00:53 - And now you get a secondary response somewhere else that now is no longer good. Good.
01:00:59 - I would argue that when it does that, because of the closing of the loops,
01:01:04 - you end up having a compensatory response also driven by the brain to try to address that.
01:01:09 - Now, maybe that compensation is too much or too little, and that causes another
01:01:12 - problem. Maybe that's how things ripple.
01:01:15 - The point is, it's very interesting that in talking to clinical colleagues,
01:01:21 - so for example, a key phenotype that happens following severe trauma,
01:01:24 - or that actually happens following underlying sepsis infection is that you get
01:01:30 - a severe blood pressure drop.
01:01:31 - In trauma, you get it because you're bleeding. In sepsis, you get it through
01:01:34 - secondary inflammatory mechanisms that create a blood pressure drop.
01:01:37 - The typical clinical response is to give fluids to raise the blood pressure
01:01:42 - or to give pressors to raise the blood pressure.
01:01:44 - Because there's going to be, of course, an impact on the heart,
01:01:47 - they're going to use inotropes as well.
01:01:50 - But one might imagine that But within a range, it would be best to leave the
01:01:54 - system alone because the sensation of the blood pressure drop is itself triggering
01:01:58 - secondary corrective responses.
01:01:59 - The flooding of the system with information driven by an outside agent actually
01:02:05 - ends up confusing the system.
01:02:07 - The system now is unable to respond appropriately because it's looking for a
01:02:10 - set of cues that it just doesn't find.
01:02:13 - And now one could argue that critical illness is that. Because critical illness
01:02:17 - cannot show up if there was no intensive care unit, if there was no,
01:02:21 - I mean, I'm not in any way trying to say that we shouldn't have medical care,
01:02:25 - but certain phenotypes are a consequence of the medical intervention.
01:02:31 - Well, I think that's an important observation, right?
01:02:32 - Because as long as you don't understand this complex network nature of the system
01:02:36 - where you're chasing symptoms, we might be only further destabilizing it as
01:02:40 - opposed to helping it to get back within the range of normal operation.
01:02:44 - And I get a sense from my clinical colleagues that they often feel like that.
01:02:48 - Our study on the survivors versus non-survivors, which was followed of trauma,
01:02:52 - which was followed by another study we published recently, where we use that
01:02:56 - population to discover novel genotypes associated with survival and non-survival.
01:03:04 - Suggests the possibility that some percent of the population is wired from the
01:03:09 - beginning to have this very rapid feed-forward inflammation,
01:03:12 - which in the context of, say, severe traumatic injury, will lead to death.
01:03:16 - The suggestion is that, and of course that is ethically scary,
01:03:21 - because the suggestion is that as things are, it will simply not be possible to rescue those people.
01:03:28 - The hope would be that the discovery of those early pathways that we've done
01:03:34 - through network analysis might lead to targeted interventions It can be given
01:03:38 - very early to reverse that, to change that.
01:03:40 - Those pathways, by the way, are not, again, nothing in inflammation is ever
01:03:44 - just inherently harmful. Those pathways are pathways that would protect you from infection.
01:03:48 - So in normal daily life, the fact that you are overly sensitive sets you up
01:03:54 - for doing way better in terms of dealing with normal infections.
01:03:57 - But now at the wrong time, in the wrong place, with a severity of injury above
01:04:02 - a certain threshold, those genetics set you up for...
01:04:06 - Progressive inflammation and
01:04:07 - death but for those in those situations your only hope is to completely.
01:04:13 - Block communication between organs right so
01:04:16 - that would be that's a very interesting point so right rather than i mean i'm an immunologist
01:04:19 - so of course my normal solution is immune but one one
01:04:23 - could imagine that an appropriate uh stimulus
01:04:26 - given centrally at the at the brain level could
01:04:29 - in fact accomplish that meaning
01:04:32 - allow the allow the local environment to do
01:04:35 - its infection fighting thing if it can while stopping
01:04:39 - the message that says keep keep cascading positive feedback yeah i agree the
01:04:45 - key is of course identifying those patients now we now have a set of um seven
01:04:50 - single nucleotide polymorphisms that are interesting because they're not a single
01:04:55 - one of them is directly involved with inflammation,
01:04:57 - as we can tell, but are more with tissue health or resilience,
01:05:02 - if you will, we're completely predictive of the non-survivor phenotype.
01:05:10 - This needs to be validated again, because we have overall only about 5% of patients
01:05:14 - will end up being non-survivors in terms of people that make it into the intensive care unit.
01:05:19 - It's a larger percent if you look at severely injured patients that just are
01:05:22 - overwhelmingly injured, right? But but 95% of patients can survive.
01:05:26 - So the idea is that, yeah, if one had the right biomarkers and one had the right
01:05:36 - therapy that could be targeted in a very precise fashion.
01:05:40 - That should be quite doable.
01:05:42 - Right, exactly. Yes. So the other thing is now is the brain involved.
01:05:46 - The brain is controlling stuff, so it can be more complex.
01:05:51 - Contextualized perturbations to the system. but I'm going to pay a price because
01:05:55 - the brain goes to screw it up.
01:05:58 - Yes. So psychological stress. So one thing that happens already that can be
01:06:02 - observed in patients that are trauma patients, even if it's not traumatic brain
01:06:06 - injury, where there's of course a direct impact to the brain,
01:06:08 - is that you get into a kind of delirium state.
01:06:11 - There's a cognitive decline that is seen in severely injured patients.
01:06:16 - So that tells you the brain is in fact paying a price.
01:06:20 - Whether it's the assumption I think before was that it's an indirect process
01:06:23 - that has to do with the fact there's overwhelming inflammation,
01:06:28 - maybe a breakdown in the blood-brain barrier.
01:06:30 - But one could argue that one way in which you achieve that is because the brain
01:06:34 - is working overtime to try to regulate the inflammatory response,
01:06:36 - or it's getting now many centers activating with these inflammatory mediators
01:06:41 - that are both neurotransmitters and inflammatory mediators and have this positive
01:06:44 - feedback characteristic.
01:06:45 - So they rapidly spin up out of control in multiple places.
01:06:49 - Then one could imagine that could lead to at least a temporary cognitive impairment.
01:06:53 - One could also imagine that if over a long period of time one has repeated stresses,
01:06:59 - repeated infections, repeated traumas, that the system again becomes overwhelmed
01:07:04 - and that sets you up for a chronic neurodegenerative disease.
01:07:07 - But I want to push the test scale, the causation in a direction.
01:07:11 - Because yes, there's a lot of information that information leads to neuropathology, right?
01:07:17 - For Alzheimer's, Parkinson's disease, there are many examples, right?
01:07:20 - Or enough examples. but maybe it
01:07:23 - can go the other way around as well that mental states rebuilt
01:07:27 - by the brain start to actually have an impact on
01:07:30 - the inflammatory states of organs in the body yes that
01:07:33 - in the end lead to your demise yes no and again that
01:07:36 - that is a been very actively tested and
01:07:39 - it's a very major area of not just investigation
01:07:42 - but now of direct clinical application there are companies that are directly
01:07:46 - stimulating the brain to be an an anti-inflammatory mechanism or therapy for
01:07:54 - things like sepsis or rheumatoid arthritis or other sort of clearly inflammatory diseases.
01:08:00 - And it's not just by coincidence. It's because of this hypothesis,
01:08:03 - because of the data behind it and so forth.
01:08:05 - What mental states can lead then to or amplify sepsis, aggravates as an example?
01:08:12 - What mental states, would you call them stress, psychological stress.
01:08:17 - Or would you call them something else? I think that has been very understudied.
01:08:22 - The problem with sepsis is that although it is very much an acute inflammatory
01:08:26 - process and it can very rapidly spin up and out of control,
01:08:30 - the clinicians typically don't see the patient until that patient has been incubating
01:08:34 - this infection for some period of time, which can vary before they show up with
01:08:39 - severe enough symptoms to the intensive care unit.
01:08:42 - So it's very tough to be able to, to make that study in trauma.
01:08:47 - The problem is that almost no trauma has zero impact on the brain to start with, right?
01:08:55 - So even if it's not a direct traumatic brain injury, there's the,
01:08:59 - of course, the massive sensation of the traumatic event.
01:09:04 - And then there's, of course, almost impossible to have the lack of any kind
01:09:08 - of anatomical impact on the head region and have an injury severe enough to
01:09:13 - actually be having the symptoms one talks about.
01:09:16 - So it's, again, one of these very tough situations where I think it's there.
01:09:20 - I think it does do what you say, where someone pre-stressed. you
01:09:24 - can you could do epidemiologic studies i think they have been done
01:09:27 - but again there's so many factors that go into that um
01:09:30 - that and you know there is
01:09:33 - this very interesting um brain related
01:09:38 - uh or apparently brain related uh study in sepsis that looks at something that
01:09:45 - you would think would be quite a negative thing so smoking so it turns out that
01:09:51 - because Because nicotine itself can trigger,
01:09:56 - you know, the nicotinic pathway can trigger anti-inflammatory mechanism.
01:10:00 - Sometimes smokers actually are doing better in sepsis. You would think it'd
01:10:04 - be the other way around since they're having compromised lung function.
01:10:07 - Right. So, of course, one wouldn't recommend people to start smoking.
01:10:09 - But it's an intriguing sort of hypothesis.
01:10:14 - Hypothesis um i think that as i said i think it would be quite likely that being in chronic stress.
01:10:24 - Will will set you up for i mean it's known that being
01:10:27 - in chronic stress will set you up for infection that that's sort of known whether
01:10:30 - the epidemiology has been done to say that you could progress from that to full-blown
01:10:35 - sepsis i'm not i i don't think consequence of what you're saying now we're told
01:10:39 - the smoker example in some sense collectively we make this naive assumption.
01:10:45 - That the healthy state is zero
01:10:49 - perturbation of the system it's this homoestatic view again we're in stasis
01:10:52 - but it is misguided because it's i was stuck it's a it's a dynamic system it's
01:10:59 - a continuous change it's continuous change that maintains the healthy state
01:11:03 - in a range appropriate responsiveness is held.
01:11:06 - We showed that. So before we did all the modeling, we showed in trauma patients
01:11:10 - and also in experimental animals,
01:11:12 - the large animal swine model of severe injury and hemorrhage,
01:11:17 - that if you didn't mount an appropriate, adequately robust, say,
01:11:23 - inflammatory response,
01:11:25 - you would be a non-survivor or you would be an animal that is not amenable to resuscitation.
01:11:32 - So a mediator that you would say oh no look there's an inflammatory response
01:11:36 - they might they're probably going to do worse actually they're the ones that
01:11:39 - are doing well because they're it's a surrogate it's a proxy for responsiveness
01:11:43 - you can show that by measuring um you know norepinephrine you can you can measure
01:11:47 - other and they track with this so,
01:11:50 - there's a the inflammatory responsiveness is just another way of saying responsiveness.
01:11:55 - So, look, Jeroen, so for me, this is all fantastic also because I'm learning a lot.
01:12:00 - And it's also beautiful to see that this compartmentalization of a naively imposed
01:12:06 - on the system, like distinguishing brain from body from immune.
01:12:10 - This has been not very helpful, right?
01:12:13 - That's where these are very intensely coupled networks.
01:12:16 - So, now you're in this domain of immunology for a long time.
01:12:20 - You also have really been sort of advancing and
01:12:23 - struggling to bring new concepts and ways of thinking
01:12:26 - into the field so if we would like to follow in in in in that tradition that
01:12:32 - you represent what would be your arm's law that we have to adhere to um i don't
01:12:38 - know that i've ever would ever see myself as positing something like that i
01:12:43 - would say that that the best thing i can
01:12:45 - say is that inflammation as a communication network is something that needs
01:12:54 - to be looked at in pretty much any system that you're trying to study biologically.
01:12:59 - I don't really have a law like these are the exact underlying structural or
01:13:06 - functional motivations of biology or something like that.
01:13:10 - I'm just not at a place where I can say anything like that. The practice of
01:13:15 - doing science, the practice of gaining knowledge about this system.
01:13:19 - Well, then that's much simpler. Yeah. I would say always interact with people
01:13:24 - from a different discipline and that think differently from you and then try
01:13:29 - to integrate as much as possible.
01:13:32 - Don't have preconceived notions.
01:13:35 - I would say that is true. Yes. Okay. So now I'm going to visit you in four years'
01:13:41 - time out there in Pittsburgh.
01:13:46 - I'm going to check the progress of research. As you know, research is hypothesis-driven.
01:13:53 - So what's the hypothesis that you want to see confirmed in that four-year time window?
01:13:58 - So these studies that we've done that suggest now this temporal sequence of
01:14:02 - inflammatory activation bring up the automatic hypothesis that the innervation
01:14:09 - of those organs that are being activated in sequence has something to do with
01:14:16 - that inflammatory response.
01:14:17 - So then the logical study is studies in which you're doing selective denervation
01:14:22 - to the bottleneck organs, if you will. So, you know, selectively denervate.
01:14:28 - So for example, the spleen, you know, selectively, it's one of the,
01:14:31 - it's essentially, we're seeing in mice, at least that that seems to be the place
01:14:34 - where inflammation occurs.
01:14:36 - Reaches its peaks the soonest. The spleen is known to be, of course, very innervated.
01:14:41 - So selectively denervate the spleen, collect the time course data,
01:14:48 - run the network analyses, and
01:14:50 - see whether the networks that you've previously seen are now collapsed.
01:14:53 - The prediction of the spleen is the hub of inflammation?
01:14:57 - For this particular mouse model. So in this particular strain of mice that's
01:15:03 - tuned to be very inflammatory and to this particular stimulus.
01:15:07 - Now we have an entire set of data that I didn't even talk about today where
01:15:11 - we subjected the same mice, the same two types of mice, to experimental trauma hemorrhage.
01:15:16 - Because it turns out that not the beauty of this is the same receptor that's
01:15:21 - being used to sense damage associated molecular pattern molecules in the case
01:15:25 - of trauma is the one that also is being sensed for lipopolysaccharide in the
01:15:30 - case of sepsis so so we could compare the two mice.
01:15:35 - Strains across time and across all the the organs right but now the stimulus
01:15:39 - is quite different It has a different characteristic.
01:15:42 - It's not a rapidly peak-shaped, you know, input influx of a very strong bacterial immunostimulant.
01:15:51 - It's now a combination of trauma with hemorrhage and secondary mechanisms.
01:15:55 - And all these organs do fail in the critically ill patients that have that.
01:16:00 - How do you summarize it in a 10-word prediction we can print on a T-shirt?
01:16:05 - For what's going to happen in the trauma hemorrhage? I would say that in the
01:16:09 - trauma hemorrhage, we were going to probably see a much more central early role
01:16:12 - for the gut, which we saw a bit later in the sort of sepsis model.
01:16:18 - But I think the bigger prediction is more that we will see networks collapsing
01:16:24 - when we denervate the bottleneck organ.
01:16:29 - Let's say the first organ that matters. We will see downstream networks collapsing.
01:16:32 - And that if we do the control study where we, let's say, denervate the last
01:16:37 - organ or somewhere in the middle, we're only going to see a partial collapse of those networks. Yes.
01:16:43 - Wonderful. Jeroen Bodevoort, thank you very much for this conversation.
01:16:47 - Thank you very much for having me on this podcast and for inviting me to BCBT.
01:16:52 - You're welcome. Terrific. Go back anytime.
01:16:57 - The CSN podcast was produced by the Convergent Science Network of Biometrics
01:17:02 - and Biohybrid Systems, a project funded by the European Sevens Research Framework Program.
01:17:10 - For more interviews, recorded lectures, or upcoming conferences in the field
01:17:16 - of biometrics and biohybrid systems, go to csnnetwork.eu.
01:17:22 - Music.

CSN Podcasts

Yoram Vodovotz on inflammation and immune system

Season 2019

Description

CSN Podcasts

Episodes

Vincent Hayward on haptics and touch

Viktor Jirsa on epilepsy and virtual brain

Stuart Wilson on self-organization and cortical maps

Marco Diana on addiction and dopamine

Lluís Fuentemilla on memory consolidation and sleep

Timestamp

Be the first to leave a comment

Leave a commentCancel

Legal

Follow us on

Yoram Vodovotz on inflammation and immune system

Description

Episodes

Timestamp

Be the first to leave a comment

Leave a commentCancel

Tags

Legal

Follow us on

Login to enjoy full advantages

Please login or subscribe to continue.

Go Premium!

Enjoy the full advantage of the premium access.

Stop following

Cancel subscription