- [Narrator] The University of Michigan
Division of Gastroenterology
and the Inflammatory Bowel Disease Program
hosts the IBD Visiting Professor Lecture Series
in Ann Arbor, Michigan.
This series presents the latest in clinical research
and basic science from IBD experts from around the world.
- [Claudio] This is, believe it or not, Cleveland.
This is downtown.
This is Lake Erie.
So going in that direction that Ann Arbor,
and this is the campus, the Cleveland Clinic
which is pretty large and impressive
and that's where I spent many, many years of my life.
- [Woman] What about your hotel, Claudio? (mumbles).
- [Claudio] The hotel?
- [Woman] (mumbles)
- [Claudio] The hotel that you stayed is
behind the tower.
- [Woman] That's what we need (mumbles).
(laughter)
- [Claudio] So, I hope that the title doesn't turn you off
too much, but I actually copied the first sentence from
a paper that you may have seen.
Hello?
In science, not too long ago, where they did the list of
the 10 most developments in the last decades, science-wise.
And as I was looking at this list of
what smart people picked,
I realized there were four crucial components that are
probably relevant to IBD.
First of all, they talk about DNA,
then they talk about the new concept of cell plasticity.
Cells are not really totally differentiated,
they probably revert into whatever is needed by the body.
And then they talk about inflammation,
obviously related to IBD.
And then they talk hardworking gut microbes.
So, these are basically four components that now are
pillars of inflammatory bowel disease.
So, I think that people that do research in IBD,
they are in good shape, well-positioned.
Because, if somebody like science say,
"These important subjects, and we're all doing them."
I think that we're probably on the right path
to find out what is IBD all about and how to manage it.
Then, I wanna go back in time
and show a slide that I developed in 1998:
"Looking back: IBD little over a decade ago."
And, if you look at what we knew,
what we thought were the components of IBD
back in the late 90s,
the genes, the environment, bacteria,
and the mechanisms in inflammation.
I think we were already on target as far as knowing
what are the key elements.
And in fact, these key components of IBD pathogenesis
are still the one that we focus on, except that now,
we have picked particular areas in particular groups
where individuals go into each one of them.
And as you start to do that,
obviously, things become more complicated,
because each one of them is an enigma in itself.
So what we have, we have a variety of components of IBD.
We go from endogenous to exogenous factors
and all of them will act
probably in a very coordinated, but still unknown way,
and cause, you know, IBD in somebody.
So this is the result of a complex pathways.
And the complexity, which is in my title,
has to do with the fact that we have many components
and we still don't understand how they fit all together.
So we have a complexity of IBD pathogenesis,
but we still have the patient, and each patient with IBD
is somewhat unique.
They have different location of the disease,
different response to therapy,
different sedimentology and so on.
So, I think what we're facing now,
we know probably what causes the disease,
not the mechanisms, necessarily,
and we have the response in the patient.
But we don't know how we have so many factors
and so many individual responses.
And starting to the pathways of looking at the factors,
if we look at the component of IBD genetics,
in 1932, Joe Kirsner and
Burrill Crohn define terminal ileitis.
It took 30 years for Joe Kirsner to say,
"Well, actually, we have these patients and families,
we have multiplicity of patient in the same family,
suggesting environmental, but moreso, genetic factors."
Then he took about another...
only little time.
I'm sorry, 30 years to get to the genome scan.
And then we found the first gene in 2001, the NOD2.
And then took only five years to find the second gene,
the IL-12 receptor.
And then now, in only few years,
we have more than a hundred genes associated with
inflammatory bowel disease.
And what we're doing now is keep accumulating
long lists of genes, loci, risk factors,
variations that are associated with
inflammatory bowel disease.
And one of the questions is, how many more genes do we have?
Now, what we know now explains about 30%
of genetic background.
So there's a lot of people that have
genetic risk factors that are very rare.
And they are associated with very small group of people.
But this represents, still, the majority.
And there is a major challenge in now understanding
how the genetic variations related to
inflammatory bowel disease.
And if you look at the NOD2, that has been around 10 years,
we still don't know how NOD2 causes terminal ileitis.
And one way, possibly, to approach this,
is to look at genes not individually, but all together,
and ask the question,
"Are genes with variations been associated with IBD
in similar pathway, so that perhaps, they belong
to complex, integrative pathways that lead to the disease?"
It's very unlikely that one single variation
in a single gene does that.
In this diagram, (mumbles),
this proposes some example like this,
in which there is variations
of the IL-12 pathway.
They are associated, probably, in the same cells,
and the combination of genetic variations
that maybe can lead to major changes in the behavior
of the (mumbles) response.
And this is true for all the other types of genes,
this being different categories of elements.
And from this
somewhat sophisticated approach of GWAS genomics,
now we start to see reports
that are not particularly impressive,
but in which we can see the trends of the IBD community
in trying to integrate big chunks of knowledge
into expression profiles, or genetic signatures.
These are not big studies, but nevertheless,
there is a hint that by studying responses
in more global fashion,
we can now, perhaps, categorize patients
into patients that will respond to Infliximab,
or fail to respond, predict surgery,
predict outcome, and so on.
So again, I think we are in the right trends,
we just need to become more sophisticated
in the analysis of genetic factors.
What I personally think that is, by far,
the most important components of IBD
is (mumbles) knowledge of IBD.
What you see here, from the dark pink to the light pink,
is the variation over time
of incidents and prevalence of IBD in different countries.
In from what was a, basically,
North American, north European disease
right after World War Second,
now we see IBD everywhere in the world,
and the last people to suffer are in the Asian continent.
So this is, to me, is a fundamental piece of information
that tell us that as we evolve as human being,
we develop Westernized, more "civilized" way of living.
Whatever we do to ourselves predispose us to IBD.
And this could be reproduced for MS, psoriasis,
and many other chronic autoimmune diseases.
So, in many ways, I think that we make
this disease for ourselves.
And what do we do to cause disease?
What have we changed in the environment?
Well, people forget that
what's in the gastrointestinal tract
is two things only, basically:
bacteria and food.
And when we ask the question, we only say,
"Well, you know, it's bad to have hamburgers
and greasy food and lot of sugars, and so on."
But we really don't understand how this impact.
And if we ask the question,
"Are food-derived components involved in IBD pathogenesis?"
Intuitively, one says, "Yeah, probably, more likely,
because the association in time and space, it's there."
But we ask the question, specifically,
"How does that happen?"
We have no clues.
Nevertheless, we are arriving to a point where we understand
that what we exposed to early in life, very early in life,
probably has a very big impact
on the development of disease later on.
This is a nice study from the (mumbles) Journal
at the end of 2010,
showing that depending on the type of milk that certain
children drink at age zero to 10 years,
has an impact on the presence of auto-antibodies,
in this particular case, for beta-cell autoimmunity.
So, the chance of developing autoimmunity in life
probably is impacted somehow
by how our immune system is educated early in life.
And this is fundamentally important because
if we're gonna cure the disease in older children,
or in teenagers and adults,
and the causes are early in life,
like in the first few months or the first few years of life,
it becomes fundamentally important to change lifestyles
when we understand what we do wrong
early in the game.