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Stepping away from the trees to look at the IBD Forest: complexity and individuality 5/5


– [Presenter] So when we look at IBD, we can no longer think
about the patient with IBD at that point in time. IBD starts early in
life, perhaps in utero, And a series of events
lead to the diagnosis, in which time we make
a therapeutic decision, but at that time when
patient’s in front of us in the office, we don’t
know what’s gonna happen to the patient. So we have life before
inflammatory bowel disease, and then we have life after IBD diagnosis, and this life can be a
good one or a bad one. The patient may or may
not respond to therapy. May need a lot of
hospitalization, may not. May need surgery or not.
May develop cancer or not. So we have to think about
IBD as a continuum that goes from early disease into late disease. And this concept is also trickling down at the practical level,
at the conscious level of the IBD community, and
we start to do the top down or bottom up therapies. And with this account, so that perhaps if we intervene early in the disease, it’s better. In fact, if the triggering
factors are really early in the disease, why wait until you have full-blown,
severe manifestation to intervene more dramatically and perhaps hopefully, more effectively? So we have a lot of factors in IBD. Probably, we still believe
that the environment, the genes that the gut
microinflammatory response are the primary factors,
but these are modulated by a variety of secondary factors. The neuroendocrine systems, the dumps, the process of angiogenesis,
the process of scarring, adipose tissue and so on. So, the picture is very complex and there’s all these interactions between all these factors, they make our life very complicated. And now, I came up with my own “ome”. How about thinking
about the “convergeome”? The converging of
factors that lead to IBD, this is an editorial by
Arthur Kaser in “Gut”. where it talks about
the convergence of the NOD pathway with the autophagy
pathway and the ER stress. And, in fact, all these
events are actually happening at the same time. We don’t quite understand
if there’s a sequence yet of events, but clearly
we can demonstrate that all these pathways activated so they’re all, it seems
we need a lot of events to actually cause the disease, or a lot of events to
maintain the disease. So of all the factors, there is this complex interacting network
that leads to IBD pathogenesis, and if we have to ask ourselves, “how do we handle this?” If we keep studying individual components, in individual models, in individuals labs, it’s hard to conceive that
we’re gonna see the pictures all together. And we have to think about this. This is something I’d really like to show. This is an editorial in Nature Immunology with a paper by Ron Germain, saying, “you have to embrace the complexity, you have to accept the fact
that diseases are complex and development pathologies, that are looking at the disease
in a global fashion. The canonical pathways
are good to get funded and are good to publish paper, but they are not good to
understand the disease. So, we have all these “omes” now. The transcriptome, the inflammasome, the resolvome, the explosome. So, how do we handle that? Actually, it’s very simple. All you have to do is
change an “e” to an “ics” and you do transcriptomics,
inflammosomics, explosomics, apoptosomics. The problem is that each one
of them is extremely complex, and what we need is collection
of huge amount of data and analyzing by system biology, where we analyze in artificial
and silicone fashion all the complexity of the data based on, hopefully, correct
assumptions, and we generate information that give us a
global picture on diseases. So, we get biopsies,
we get blood and so on. We get a large bottles of molecular data, we analyze construction of models and then we need to start to
define outcomes signature. If the patient had the mother was obese and he took antibiotics early life and then was exposed
to a clean environment and he was in hospital many
times, perhaps he will have a bad signature of a bad disease, like you get diagnosed
is not after the fact, but early in life and vice
versa for a good outcome. And obviously would be
tremendously important in predicting if this patient
will need early intervention or more aggressive therapy or not. I don’t think we’re every
gonna be able to change the natural history of disease. But we can modulate it
for the better once we are diagnosed with the disease. So, going back to the forest,
this I actually a picture from the Amazon forest where I go fishing. I didn’t show the picture
of fishing this time, but maybe next time. And this is a nice river,
this is a beautiful forest, virgin forest, and this is like IBD. So what do we do? So, we need to create
genetic, environmental, microbial and immune signatures. And we’re not quite ready yet, but at least we are aware of that. So, the “omes” that I
mentioned are here to stay. And probably understanding
the “omes” holds the key to inflammatory bowel disease and the omics are the
techniques that we start to need to apply to understand the omes. Perhaps with this approach
combining the omes with the omics we can understand both the
complexity of the disease and the individuality of
the patient’s response. Thank you. (Applause) Any questions? I’ll be glad to answer. – [Female Audience Member]
Clearly, that was wonderful as usual. Did I hear you correctly, though, that you don’t think that we’re
gonna be able to alter the actual history of the disease? – Nah. – [Female Audience Member]
You don’t think anti-T and Fs can inflict some (spoken over)
– Nah! – [Female Audience Member]
Qualities alter the natural history of the disease? – Once you’ve have the disease
diagnosed, it’s too late. You might make the patient better, but the disease will never go away. To me, changing natural history means not making the patient better, we’ve been doing that for years. It’s to make the disease go away. – [Female Audience Member]
So cure, essentially. – Yeah! That’s really a change. – ‘Cause we’ve, surprisingly been able to reset people, not always on purpose, but they’ve been doing bone marrow transplants. – Mm-hmm (affirmative). – But it’s interesting that
eventually it comes back. Without any other initiating events. – The question is, are the same environmental triggering factors changed? Because if you have, let’s suppose that your triggering factor
is something which is post-natal and your living
the same environment was still there. Maybe there’s enough
to maybe form a disease but give you the disease because
there are multiple genes. So, it is possible, but
then you really basically changed the whole composition
of an individual that way. And that’s possible, I
think it’s believable to change the natural history and eliminate the disease that way. I think it’s possible. But then you’re no longer yourself, you’re a chimera. – Well, they claim and
I suppose the surgeons say that they’re resetting. – Yeah, people love the word “resetting,” you know, Steph Tagrin
used that 20 years ago. And still we haven’t reset it. (laughs) – [Male Audience Member]
So, you went on about you guys reached interesting,
have you tried at any point what other target cells
are you compiling data? I mean, are you looking at all of them? – All the cells are,
because all the cells have our receptor. – [Male Audience Member]
But that is with the soma, did you try to do it in patient tissue? Like if there was an increased
in IL-1 alpha receptors, or, that you specifically aided. – Yeah, those studies
have actually been done 10, 15 years ago. There is an increase of
IL-1 receptors, y’know there was a time when
IL-1 was defined as if strong biological factors endocrine. So I will want there is a balance between all these family members have anti-inflammatory activity,
pro-inflammatory activity. And they are two types of receptors. They are receptor I which is an agonist and there are receptors II,
or I receptor antagonist they, y’know, block the response. So, the balance between
the type I and type II determines how much you see as
far as inflammatory signals. But now, y’know, for instance, the neurologist reported
Il-37, which is interleukin-1 which is a strong inhibitor
of native immune responses. So, they are one family,
it’s really very fundamental to a native immune response,
to the acute responses. And IL-1 alpha is one of the components. IL-1 alpha are not usually
seen in a healthy conditions, because it’s not secreted and all the job is done
by interleukin-1 beta. But once the cells die, obviously, you add to this pro-inflammatory assault. – [Female Audience Member]
I think the dermatologists are really interested in that IL-1 family ’cause it’s important
in the proliferation of the epithelial cells. – Oh yeah, and actually, keratinocytes were the
first cells to be described to produce huge amounts
of interleukin-1 alpha. Y’know, there was a paper
in Genetics Med in, well 25 years ago on that. – [Female Audience
Member] I was wondering if y’know, probably the epithel–
noticed all the action associated with IL-1 alpha is
epithelial that you showed. – That’s a system we used
because the epithelial cells, they’re easiest to damage. – [Female Audience Member]
Right, I wonder, y’know, the epithelial phenomena
that’s probably the most unique to IBD is the crypt abscess, and that seemed to be a perfect setup for a little pocket of huge
amounts of IL-1 alpha if you have a chance to look
at human tissue or models where you get a lot of crypt abscesses? – Not particularly, no. But I don’t think you need
to have the crypt abscess to have tons of IL-1
alpha, you have it anyway. But it’s interesting about
that when you look at this most good histological pictures, the crypt cells are intact, right? You don’t see ulcers and,
usually the classical picture of crypt that you see the
neutrophils in the crypt, but the epithelial cells is intact. So, that’s probably
just the migration, but somewhere else in the vicinity there is tissue destruction, undoubtedly. And obviously, they’re not just IL-1 alpha that cause inflammatory infiltrates and neutrophils infiltrates. Yeah, we tend to expecting
in vivo the models we use which are very restricted and convenient.

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