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  • 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,