Can we regenerate heart muscle with stem cells Chuck Murry

I’d like to tell you
about a patient named Donna.

In this photograph,
Donna was in her mid-70s,

a vigorous, healthy woman,

the matriarch of a large clan.

She had a family history
of heart disease, however,

and one day, she had the sudden onset
of crushing chest pain.

Now unfortunately, rather than
seeking medical attention,

Donna took to her bed for about 12 hours
until the pain passed.

The next time she went
to see her physician,

he performed an electrocardiogram,

and this showed that she’d had
a large heart attack,

or a “myocardial infarction”
in medical parlance.

After this heart attack,
Donna was never quite the same.

Her energy levels progressively waned,

she couldn’t do a lot of the physical
activities she’d previously enjoyed.

It got to the point where she couldn’t
keep up with her grandkids,

and it was even too much work
to go out to the end of the driveway

to pick up the mail.

One day, her granddaughter
came by to walk the dog,

and she found her grandmother
dead in the chair.

Doctors said it was a cardiac arrhythmia
that was secondary to heart failure.

But the last thing that I should tell you

is that Donna was not just
an ordinary patient.

Donna was my mother.

Stories like ours are,
unfortunately, far too common.

Heart disease is the number one killer
in the entire world.

In the United States,

it’s the most common reason
patients are admitted to the hospital,

and it’s our number one
health care expense.

We spend over a 100 billion dollars –
billion with a “B” –

in this country every year

on the treatment of heart disease.

Just for reference, that’s more than
twice the annual budget

of the state of Washington.

What makes this disease so deadly?

Well, it all starts with the fact that
the heart is the least regenerative organ

in the human body.

Now, a heart attack happens when
a blood clot forms in a coronary artery

that feeds blood to the wall of the heart.

This plugs the blood flow,

and the heart muscle
is very metabolically active,

and so it dies very quickly,

within just a few hours
of having its blood flow interrupted.

Since the heart can’t
grow back new muscle,

it heals by scar formation.

This leaves the patient with a deficit

in the amount of heart
muscle that they have.

And in too many people,
their illness progresses to the point

where the heart can no longer keep up
with the body’s demand for blood flow.

This imbalance between supply and demand
is the crux of heart failure.

So when I talk to people
about this problem,

I often get a shrug
and a statement to the effect of,

“Well, you know, Chuck,
we’ve got to die of something.”

(Laughter)

And yeah, but what this also tells me

is that we’ve resigned ourselves to this
as the status quo because we have to.

Or do we?

I think there’s a better way,

and this better way involves the use
of stem cells as medicines.

So what, exactly, are stem cells?

If you look at them under the microscope,
there’s not much going on.

They’re just simple little round cells.

But that belies two remarkable attributes.

The first is they can divide like crazy.

So I can take a single cell,
and in a month’s time,

I can grow this up to billions of cells.

The second is they can differentiate
or become more specialized,

so these simple little round cells
can turn into skin, can turn into brain,

can turn into kidney and so forth.

Now, some tissues in our bodies
are chock-full of stem cells.

Our bone marrow, for example, cranks out
billions of blood cells every day.

Other tissues like the heart
are quite stable,

and as far as we can tell,
the heart lacks stem cells entirely.

So for the heart, we’re going to have
to bring stem cells in from the outside,

and for this, we turn to
the most potent stem cell type,

the pluripotent stem cell.

Pluripotent stem cells are so named

because they can turn into
any of the 240-some cell types

that make up the human body.

So this is my big idea:

I want to take human
pluripotent stem cells,

grow them up in large numbers,

differentiate them
into cardiac muscle cells

and then take them out of the dish

and transplant them into the hearts
of patients who have had heart attacks.

I think this is going to reseed the wall
with new muscle tissue,

and this will restore
contractile function to the heart.

(Applause)

Now, before you applaud too much,
this was my idea 20 years ago.

(Laughter)

And I was young,
I was full of it, and I thought,

five years in the lab,
and we’ll crank this out,

and we’ll have this into the clinic.

Let me tell you what really happened.

(Laughter)

We began with the quest to turn these
pluripotent stem cells into heart muscle.

And our first experiments worked, sort of.

We got these little clumps of beating
human heart muscle in the dish,

and that was cool,
because it said, in principle,

this should be able to be done.

But when we got around
to doing the cell counts,

we found that only one
out of 1,000 of our stem cells

were actually turning into heart muscle.

The rest was just a gemisch
of brain and skin and cartilage

and intestine.

So how do you coax a cell
that can become anything

into becoming just a heart muscle cell?

Well, for this we turned
to the world of embryology.

For over a century, the embryologists
had been pondering

the mysteries of heart development.

And they had given us
what was essentially a Google Map

for how to go from a single fertilized egg

all the way over to a human
cardiovascular system.

So we shamelessly absconded
all of this information

and tried to make human cardiovascular
development happen in a dish.

It took us about five years, but nowadays,

we can get 90 percent of our stem cells
to turn into cardiac muscle –

a 900-fold improvement.

So this was quite exciting.

This slide shows you
our current cellular product.

We grow our heart muscle cells
in little three-dimensional clumps

called cardiac organoids.

Each of them has 500 to 1,000
heart muscle cells in it.

If you look closely, you can see these
little organoids are actually twitching;

each one is beating independently.

But they’ve got another trick
up their sleeve.

We took a gene from jellyfish
that live in the Pacific Northwest,

and we used a technique
called genome editing

to splice this gene into the stem cells.

And this makes our heart muscle cells
flash green every time they beat.

OK, so now we were finally ready
to begin animal experiments.

We took our cardiac muscle cells

and we transplanted them
into the hearts of rats

that had been given
experimental heart attacks.

A month later, I peered anxiously
down through my microscope

to see what we had grown,

and I saw …

nothing.

Everything had died.

But we persevered on this,
and we came up with a biochemical cocktail

that we called
our “pro-survival cocktail,”

and this was enough to allow
our cells to survive

through the stressful process
of transplantation.

And now when I looked
through the microscope,

I could see this fresh, young,
human heart muscle

growing back in the injured wall
of this rat’s heart.

So this was getting quite exciting.

The next question was:

Will this new muscle beat in synchrony
with the rest of the heart?

So to answer that,

we returned to the cells that had
that jellyfish gene in them.

We used these cells essentially
like a space probe

that we could launch
into a foreign environment

and then have that flashing
report back to us

about their biological activity.

What you’re seeing here
is a zoomed-in view,

a black-and-white image
of a guinea pig’s heart

that was injured and then received
three grafts of our human cardiac muscle.

So you see those sort of diagonally
running white lines.

Each of those is a needle track

that contains a couple of million
human cardiac muscle cells in it.

And when I start the video,
you can see what we saw

when we looked through the microscope.

Our cells are flashing,

and they’re flashing in synchrony,

back through the walls
of the injured heart.

What does this mean?

It means the cells are alive,

they’re well, they’re beating,

and they’ve managed
to connect with one another

so that they’re beating in synchrony.

But it gets even more
interesting than this.

If you look at that tracing
that’s along the bottom,

that’s the electrocardiogram
from the guinea pig’s own heart.

And if you line up the flashing
with the heartbeat

that’s shown on the bottom,

what you can see is there’s a perfect
one-to-one correspondence.

In other words, the guinea pig’s
natural pacemaker is calling the shots,

and the human heart muscle cells
are following in lockstep

like good soldiers.

(Applause)

Our current studies have moved into
what I think is going to be

the best possible predictor
of a human patient,

and that’s into macaque monkeys.

This next slide shows you
a microscopic image

from the heart of a macaque that was given
an experimental heart attack

and then treated with a saline injection.

This is essentially like
a placebo treatment

to show the natural history
of the disease.

The macaque heart muscle is shown in red,

and in blue, you see the scar tissue
that results from the heart attack.

So as you look as this, you can see how
there’s a big deficiency in the muscle

in part of the wall of the heart.

And it’s not hard to imagine
how this heart would have a tough time

generating much force.

Now in contrast, this is one
of the stem-cell-treated hearts.

Again, you can see
the monkey’s heart muscle in red,

but it’s very hard to even see
the blue scar tissue,

and that’s because we’ve
been able to repopulate it

with the human heart muscle,

and so we’ve got this nice, plump wall.

OK, let’s just take a second and recap.

I’ve showed you
that we can take our stem cells

and differentiate them
into cardiac muscle.

We’ve learned how to keep them alive
after transplantation,

we’ve showed that they beat
in synchrony with the rest of the heart,

and we’ve shown that we can scale them up

into an animal that is the best possible
predictor of a human’s response.

You’d think that we hit all the roadblocks
that lay in our path, right?

Turns out, not.

These macaque studies also taught us

that our human heart muscle cells created
a period of electrical instability.

They caused ventricular arrhythmias,
or irregular heartbeats,

for several weeks after
we transplanted them.

This was quite unexpected, because
we hadn’t seen this in smaller animals.

We’ve studied it extensively,

and it turns out that it results
from the fact that our cellular graphs

are quite immature,

and immature heart muscle cells
all act like pacemakers.

So what happens is,
we put them into the heart,

and there starts to be a competition
with the heart’s natural pacemaker

over who gets to call the shots.

It would be sort of like

if you brought a whole gaggle of teenagers
into your orderly household all at once,

and they don’t want to follow the rules
and the rhythms of the way you run things,

and it takes a while to rein everybody in

and get people working
in a coordinated fashion.

So our plans at the moment

are to make the cells go through
this troubled adolescence period

while they’re still in the dish,

and then we’ll transplant them in
in the post-adolescent phase,

where they should be much more orderly

and be ready to listen
to their marching orders.

In the meantime, it turns out
we can actually do quite well

by treating with
anti-arrhythmia drugs as well.

So one big question still remains,

and that is, of course, the whole purpose
that we set out to do this:

Can we actually restore function
to the injured heart?

To answer this question,

we went to something that’s called
“left ventricular ejection fraction.”

Ejection fraction is simply
the amount of blood

that is squeezed
out of the chamber of the heart

with each beat.

Now, in healthy macaques,
like in healthy people,

ejection fractions are about 65 percent.

After a heart attack, ejection fraction
drops down to about 40 percent,

so these animals are
well on their way to heart failure.

In the animals that receive
a placebo injection,

when we scan them a month later,

we see that ejection
fraction is unchanged,

because the heart, of course,
doesn’t spontaneously recover.

But in every one of the animals
that received a graft

of human cardiac muscle cells,

we see a substantial improvement
in cardiac function.

This averaged eight points,
so from 40 to 48 percent.

What I can tell you
is that eight points is better

than anything that’s
on the market right now

for treating patients with heart attacks.

It’s better than everything
we have put together.

So if we could do
eight points in the clinic,

I think this would be a big deal
that would make a large impact

on human health.

But it gets more exciting.

That was just four weeks
after transplantation.

If we extend these studies
out to three months,

we get a full 22-point gain
in ejection fraction.

(Applause)

Function in these
treated hearts is so good

that if we didn’t know up front
that these animals had had a heart attack,

we would never be able to tell
from their functional studies.

Going forward, our plan
is to start phase one,

first in human trials here at
the University of Washington in 2020 –

two short years from now.

Presuming these studies
are safe and effective,

which I think they’re going to be,

our plan is to scale this up
and ship these cells all around the world

for the treatment of patients
with heart disease.

Given the global burden of this illness,

I could easily imagine this treating
a million or more patients a year.

So I envision a time,
maybe a decade from now,

where a patient like my mother
will have actual treatments

that can address the root cause
and not just manage her symptoms.

This all comes from the fact
that stem cells give us the ability

to repair the human body

from its component parts.

In the not-too-distant future,

repairing humans is going to go

from something that is
far-fetched science fiction

into common medical practice.

And when this happens,

it’s going to have
a transformational effect

that rivals the development
of vaccinations and antibiotics.

Thank you for your attention.

(Applause)