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I am at the Gladstone Institutes,
and we are a disease-focused basic science institute,
so we focus on three major diseases--
diseases of the heart, of the brain,
and viral diseases.
And in each of these areas,
We've assembled teams of individuals
that are multidisciplinary,
that are focusing on these disease areas.
And what I think we've been able to uniquely do
in the last five, six years
with great assistance from CIRM
is to develop a stem cell center that's overlaid
upon this deep knowledge of disease.
And so, with a variety of models at hand,
being able to apply the approaches and techniques
and knowledge from stem cell biology
on those diseases has really made a enormous difference for us.
And I think it's safe to say--
and I say this to many people, and I'll say it to all of you
since I have the opportunity to address you--
that our program-- stem cell program at Gladstone
would not be a fraction of what it is
in the absence of the support
we've received from CIRM through competitive grants.
And I'm very grateful of that.
And of course,
a highlight of our program and of our field
and the efforts here in California,
one of our investigators, Shinya Yamanaka,
just received the Nobel Prize, as you all know.
And I thought I'd share a photograph
from the award ceremony and the banquet
of Shinya and myself,
and it was a great privilege to be there.
But, again,
having somebody like Shinya come to--
at least, in part, to California
was in no small part due to the unique atmosphere
that we have in this state
compared to other regions of the country.
Now, the...
the clinical issue that has driven my scientific interest
for over 15 years is shown here.
I am trained as a pediatric cardiologist,
and everything we have done in the laboratory has been driven
by our interest in this disease.
And diseases of the heart in children
are very different from diseases of the heart in the adult.
They're essentially problems of cell fate determination
early during embryogenesis
when a cell is supposed to be instructed to become a heart cell
but fails to do so.
And in the end, a child is born
where parts of their heart may be missing or malformed.
And this remains the leading non-infectious cause of death
in the United States
and in most countries now around the world.
And so while we have made great strides
in managing this disease and treating this disease,
we're still clearly not doing enough
because we're losing too many children from this.
We also recognize that as we understood--
begin to understand how nature normally forms a heart,
that we might be able to leverage that same information
to even treat adult forms of heart disease
where, essentially, parts of the muscle cells
in the heart have been lost,
and we need to re-create new muscle.
With the notion that if we just use nature's own toolbox
of how it builds a heart,
we might be able to create new heart cells
in adults who need it,
because they've lost heart muscle from heart attacks
or other forms of cardiac failure.
And I'll show you, towards the end of the talk,
that we have in fact been able to do exactly that
over the last few years.
And so the story really starts by efforts
to understand how nature builds a heart.
And what I'll show you on this slide
is a schematic diagram of some of the steps
of cells being instructed to form a heart
in a very early embryo
in this image at about two weeks of gestation
on your left.
These cells align themselves in a shape
that doesn't look anything like the heart,
but they're already being told to become heart cells.
And they go through a series of steps that are shown here,
that I won't go into the details of for the sake of today's talk,
but just recognize that in most animal species,
we can trace out these steps.
And as we began to ask,
"What genes are controlling these steps?"
we began to understand how this process occurs.
Now, some of the earliest steps when the cell fate is being decided
were very difficult to tease out
in an animal-- in the embryonic system
because it all happens so quickly, within hours.
And so it was for that
that we turned to the embryonic stem cell,
or pluripotent stem cell system, some years ago,
because there in a dish, we could capture within hours
the developmental switches that are occurring
that take a pluripotent stem cell
and take it down, as you see here,
in a series of steps
to ultimately become either a cardiac muscle cell,
or an endothelial cell,
or vascular smooth muscle cell,
all of which are very important
to build the human heart.
And we now know
exactly what progenitors occur at each stage
and we can essentially recapitulate
what happens in vivo in a dish with embryonic stem cells
and induce pluripotent stem cells.
And so, together,
my laboratory, Benoit Bruneau,
who's also with me at Gladstone in the Department of Pediatrics,
and others in our field,
we have undertaken to essentially map
the entire network of genes
that control heart formation--
sort of, if you will, the blueprint
of how the heart is built.
And very recently, with the support of CIRM, we...
Benoit Bruneau had led an effort that was published in "Cell"
that essentially mapped the epigenetic
events that occur during different stages
of stem cell differentiation into a cardiomyocyte.
And this beings to give us a foothold
into the genome-wide events
that are occurring as cardiac fates are decided.
And so, if you look at a subset
of those networks that are shown here--
and these genes on this slide, the names are not important,
but they represent
sort of the major nodal points, if you will,
of the regulation of thousands of genes.
And what you can see
is that each of these color-coded progenitor cells,
the yellow ones, the red ones,
are controlled by networks that we now understand.
And it was our hope that if we understood the networks
that normally controlled these progenitors,
that in fact those might be the networks
that are disrupted in the setting of human disease.
And it's been satisfying that that, in fact, is the case.
And work from our laboratory and many other laboratories
studying the human genetics of congenital heart disease
have revealed that genes--
many genes in these pathways that I show you here
are in fact mutated
in human-- in children with disease.
And I've indicated those with asterisks
in this slide.
What I'd like you to note is that each of these pathways
appears to be hit more than once
with different genes,
and in particular, this group of-- this cluster here,
where there are three different genes--
GATA4, TBX5, and NKX.
Each of these three genes, when mutated in humans,
causes exactly the same type of cardiac disease.
And we think that's because they all physically interact
with one another
and control the same pathways.
And when those genes are mutated,
children are born with holes in their heart--
in the different chambers of the heart.
And so, some of those genes
that are shown by asterisks on the last slide
are shown in tabular form here.
And I'll just draw your attention to a few of these--
Gata4 I mentioned to you is the one that caused holes in the heart
that you see here.
Our laboratory also identified
patients that had aortic valve abnormalities
ranging from severe ones that presented at birth
to those that didn't present until later in life
because the valves became calcified and stiff
and needed to be replaced surgically.
While we've identified these gene mutations many years ago--
you'll see there we published these
in "Nature" 2003 and 2005,
we hit a roadblock.
We tried to make mouse models of these conditions
and, in every case, they taught us a little bit
but fell short of really informing us
about why these genetic mutations actually cause disease.
And at the end of the day, if you just understand the genetics
but can't go from there to mechanism,
you can't get very far
in being able to change the way you treat people.
And so the real breakthrough
came with Shinya Yamanaka's discovery
of induced pluripotent stem cells,
as you all are familiar with,
because this finally allowed us
to take skin samples-- or blood samples now--
from these patients, turn them into iPS cells,
then differentiate them into the appropriate cell type
that now we have in front of us in a dish to both--
to understand--
to use not only for cell-based therapies,
but to more importantly-- for this case,
understand why the disease is occurring
because we finally have access to the cells,
and now to begin to screen for drugs
that could alter the natural history of those--
that disease process.
So if you wanna do this-- and people, of course,
are doing this for their favorite disease,
and CIRM has been really actively supporting these--
these types of studies for many, many different types of diseases--
the prerequisite to this notion
is that you have to efficiently be able to turn the iPS cells
into the cell type that's being affected by disease.
And that's actually no small task.
And we've made great strides in the last few years,
particularly in the cardiac cell types,
to be able to now make cardiomyocytes
that are about 70% pure in the dish,
endothelial cells that are about 95% pure,
and smooth muscle cells we're still working on,
but we can get about 50% purity.
And so, as an example of this,
I'll just show you--and I'm sure you all have seen this before--
but these are human iPS cells
that have been turned into beating cardiomyocytes,
and if we stain these cells for a cardiac marker,
about 70% of cells on this dish
are, in fact, cardiomyocytes that are beating in synchrony,
and, therefore, are electrically coupled.
And so, with this in hand now,
we have proceeded to generate iPS cells
from patients with the--
family members with mutations in NOTCH 1 as I mentioned,
GATA4--these are all families that I took care of
as a clinician
in the past.
And so we have about five or six people with disease,
with the mutations, and the same number without,
all related--
in these family members.
And I won't have time to go into the details for your today,
but what I can tell you is that in each of these areas--
for mutations in elastin, as well,
that cause a smooth muscle disease,
endothelial cells with the Notch mutation,
cardiomyocytes with the GATA4 mutation--
we have been able to figure out
mechanisms by which these gene mutations
are actually causing disease--
what genes they're regulating, how it's disrupted,
to the point that we're now beginning to screen for drugs
that will alter or reverse
the pathophysiology in each one of these diseases.
We could not have done this
without the use of stem cell technologies,
and did not do it for five years
even we had discovered these gene mutations,
so I think this is an illustration
of the power of this technology.
And none of this work is published as yet,
but you'll see this come out
in the next year to year-and-a-half.
Now, that illustrates the utility of stem cell technologies
for disease modeling and understanding
and treating disease from a drug-therapy approach.
What about regenerative medicine?
There are clearly many forms of congenital heart disease
and adult heart disease
that really require us
to build new parts of the heart.
And the most dramatic one is shown here.
These are real ultrasounds
of kids who have been born with either--
what we call a hypoplastic right ventricle,
where their right ventricle of the heart is missing
but the other three chambers--
the left ventricle and the two atrial chambers are present--
and on your right is a child with a hypoplastic left ventricle,
where the left ventricle is missing
but the other three chambers are present.
There are a series of surgeries we can do now
that really alter the plumbing with these hearts
that allow these children to survive,
and that's wonderful.
But you'll hear from a patient advocate after my talk
who has a child with a small--
who was born without a left ventricle,
and you'll hear about the issues
that they face even as they go forward
after these surgeries.
And it's significant.
And the only way to really address this long-term, then,
is to be able to somehow
build a new left ventricle.
Or sometimes children are born without a valve;
we need to build a new valve.
Or they're born without a vessel
that's important for taking blood away from the heart,
so we need to build a new vessel.
And in each of these cases,
this really now has become an engineering hurdle.
As I showed you, in the last three or four years,
I think we've largely solved the problem
of getting a stem cell to adopt a specific fate.
We haven't done it perfectly yet,
but we've done it well enough in two dimensions, on a dish,
that we can get the cells we want.
That was not the case four years ago.
We couldn't get the cells we wanted.
We can do that now.
So the next hurdle is to begin to fashion these cells
in the right three-dimensional state
to begin to address these sorts of regenerative medicine issues.
And so the very next person I'm trying to recruit to Gladstone,
then, is a bioengineer to put he or she into the mix
with the chemist, the computational biologist,
the stem cell biologist,
that we have on the same floor,
and let those people go at it
and do their magic in this multidisciplinary fashion.
I think that's where the next breakthroughs will come from.