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