this Ted Talk features cardiovascular biology researcher Chuck Murray recorded live at Ted Eck Seattle 2018 Hey, parents, have you been looking for ways to engage your kids with entertaining and educational content? Or maybe you're just trying to limit their screen time. Check out Pinna. It's the only audio streaming service for kids 33 12 with original podcasts, music and audio books, all without ads. Pinna is a Parent's Choice Foundation Gold Award winner and Kids Safe certified. Visit pinna dot f m slash tet To start your 30 day free trial today, that's P I and a dot f M slash ted,

I'd like to tell you about a patient named Donna. This photograph Donna was in her mid seventies vigorous, healthy woman, the matriarch of a large clan. She had a family history of heart disease. However, in 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 my cardio 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. I got to the point where she couldn't keep up with their 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 a grandmother dead in the chair. Doctor 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 that patients are admitted to the hospital. That's our number one health care expense. We spent over $100 billion.1,000,000,000 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. So 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 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 bodies 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 effective Well, you know, Chuck, we got to die of something and yeah, but what this also tells me is that we've resigned ourselves to this is 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 there, 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 could grow this up to billions of cells.

The second is they condemn Ferentz. She ate or become more specialized. So these simple little round cells can turn into skin in turn, into brain can turn into kidney and so forth. Some tissues in our bodies are chock full of step cells are 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 laxed and 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 pleura. Potent 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've had heart attacks. I think this is going to receive the wall with new muscle tissue, and this will restore contract. I'll function to the heart now before you applaud too much. This is my idea 20 years ago, and I thought I was young. I was 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. We begin 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 he got around to doing the cell counts we found that only one out of 1000 of our stem cells were actually turning into heart muscle. The rest was just a commish off brain and skin and cartilage and intestine. So how do you coax a cell that could become anything into becoming just the heart muscle cell? Well, for this we turn to the world of embryology, and for over a century, the embryologists have been pondering the mysteries of heart development. And they had given us what was essentially, ah, 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% of our stem cells to turn into cardiac muscle.

So a 900 fold improvement. So this is quite exciting. This slide shows you are current cellular product. We grow, we grow our heart muscle cells in little three dimensional clumps called cardiac organize. Each of them has 500 to 1000 heart muscle cells in it. If you look closely, you can see these little organ oId czar 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 displaced this gene into the stem cells. And this makes our heart muscle cells flash green every time they'd be okay. 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 have 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 her pro survival cocktail. And this was enough to allow ourselves 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, which 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. So what you're seeing here is a zoomed in view. It's a black and white image of a guinea pig's heart that was injured and then received three graphs of our human cardiac muscle. So you see those sort of diagonally running quite minds. Each of those is a needle track that contains a couple of 1,000,000 of human cardiac muscle cells in it.

And when I start the video, you can see what we saw when we looked through the microscope ourselves, air flashing and they're flashing in sync pretty 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 pigs own heart. And if you line up the flashing with the heartbeat that shone on the bottom, which you can see is there is a perfect 1 to 1 correspondence. In other words, the guinea pigs.

Natural pacemaker is calling the shots. In the human heart, muscle cells are following in lockstep like good soldiers. So 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. Yeah, this next slide shows you a microscopic image from the heart of a macaque that was treated. It 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 then blue. You see this scar tissue that results from the heart attack. So as you look at this, you can see how there's a big deficiency in the muscle in the 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 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. That's because we've been able to re populate it with the human heart muscle. And so we've got this nice, plump wall. Okay, 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 learned how to keep them alive. After transplantation, we 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 macaques studies also taught us they're 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 haven't seen this in smaller animals. We've studied it extensively, and it turns out that it results from the fact that our cellular grafts 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 rain 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 adolescents period while they're still in the dish, and that shouldn't. 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, when healthy macaques like unhealthy people, ejection fractions are about 65%. After a heart attack, ejection fraction drops down to about 40%. So these animals are well on their way to heart failure, and the animals receive a placebo injection. When we scanned 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 average eight points, so from 40 to 48%. 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. An ejection fracture function in these treated hearts is so good that if we didn't know upfront that these animals that had a heart attack, we would never be able to tell from their functional stuff.

Excuse me? They're functional studies. So going forward, our plan is to start phase one first in human trials here at the University of Washington in 2022 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 shipped 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 1,000,000 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 be something that is going to go from something that is far fetched science fiction into common medical practice. And when this happens, it's gonna have a transformational effect that rivals the development of vaccinations and antibiotics. Thank you for your attention.

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