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				How to Make a Nose Tissue engineers build a nose, heart muscle, and even a retina from the ground up. (Updated from earlier broadcasts)
		Select text to jump ahead in the clip: ALDA: It's never been hard to put together body parts... in the movies. It's alive. It's alive, it's alive! It's alive! ALDA: But Hollywood better look out, because MIT scientists are getting in on the act. Does he have the nose? Yeah, it's coming. You got it? MAN: Yeah. That's the nose? It's right in the dish here. ALDA: Okay, now, we are not-- repeat, not-- on a movie set. ALDA: Wait, what is this? This is cartilage. It is a scaffold of... You see the nostrils? Oh, yuck, wait a minute. Look, with nostrils and everything. We made a scaffold and there's the little nostrils there, and that's pure cartilage. You could make it in big blocks and carve whatever shape you want. Exactly, exactly, that's the whole idea. Would you mind taking this back? I really don't want to... I mean, it's alive, it's sort of alive. Yeah, sort of alive. We just wanted to give you a flavor for it. ( laughs ) Unbelievable! You bring in a nose! I mean, that's... I can't get over that. ALDA: In MIT's Langer Lab, they're actually figuring out how to make body parts. WOMAN: First we make what we call a polymer scaffold, and that's a piece of synthetic material that we can make into the form of a sheet or other three- dimensional forms. ALDA: Now we're making heart muscle starting with little clumps of synthetic fibers-- the polymer scaffold, as they call it. Then the scaffold is bathed in living heart cells. Bob Langer has pioneered this new field of tissue engineering. LANGER; She's trying to mimic outside the body what actually happens inside the body. She's giving it the kind of food it needs, the kind of structure it needs, and even the kind of mixing, you know, that it may get inside the body. ALDA: If you get the conditions just right, you can grow pieces of living heart tissue. I'm looking at something that's making heart. Does that sort of strike you every once in a while that you're making these things that used to be if you lost it, that would be the end? Yeah, well, that's what we want to do, you know. It does strike us. What we hope is that someday we'll be able to have a whole series of replacement parts for people so if they find a problem, we'll be able to help them. It's like an auto part shop, you know. That's right. I need a new carburetor, and you just go in and you drive out again. I mean, this is... How many years away are we from having a part shop for bodies, I mean, where you really can just get what you need? Is it ten years, 50 years, a hundred years, w-what? Must be hard to guess. Right, I think it may depend on the part, you know. Some of the easier parts like skin or cartilage, I think, you know, that's probably five or ten years. Some of the harder parts, like heart, that may be many, many, years away-- 50 or, you know... it's hard to know. ALDA: Here, after about two weeks of growth, are the pieces of new heart. They're under a microscope, and then you can see it on that monitor? That's right, we have a microscope here, and then basically they're on the monitor and you can see them beating. ALDA: That's not the dish shaking; those are separate cells beating. Right-- say, take a look right down here, for example, or here. And these are individual heart muscle cells and they're just beating. Is there any way you could make use of that right now in a heart? It's too early to do that now, but someday what I expect is that we could make a sheet of this, you know, and make cardiac muscle, and someday, if we have the right type of cells, to actually transplant that onto a patient, you know, if they have, uh... you know, if some of their heart muscle's damaged. ALDA: Right now they're working with animal cells, but Bob Langer's hope is not at all farfetched. Take a look at one of those pieces of heart as they give it an EKG-- like a regular heart checkup you might get from your doctor. ( monitor beeping rhythmically ) The new tissue transmits heartbeats exactly as it should. With tissue engineering advancing rapidly, the search is on for a reliable and ethical source of human cells to grow parts from. Three years ago, I visited Michael West at his company, Advanced Cell Technology. He's aiming to make any kind of cell required, starting from the kind of cell we all came from. They're called embryonic stem cells. Embryonic stem cells are the first cells that grow as an embryo develops-- precursors to all body parts. The idea is to grow these stem cells inside unfertilized eggs, which may pose fewer ethical problems than using fertilized embryos. Go straight in? Yeah, straight in. ALDA: The technique is similar to the one used to clone Dolly the sheep, although I'm actually working with a cow egg here. First I have to pierce it and suck out the nucleus, containing the cow's genetic material. SCIENTIST: Okay, now, turn it. ALDA: There it is, here it comes. Watch this, watch this, guys-- this is good, this is good. Have I got it? Go back a little bit more. Okay, got it, got it. Perfect, right there is perfect. ALDA: Next I pick up a human cell; this one's an adult skin cell-- it could be mine or yours or anybody's. Then I slide the skin cell into the egg. ALDA: This is really fascinating to do, but what are you getting out of this? What do you hope to get out of this? Well, the excitement about cloning isn't that we can make a genetic copy of a sheep or a goat. It's that it teaches us some really fundamental biology, and that's that every cell in our body, like the skin cells, has a genetic potential to recreate life, young life. So our hope is that someday, elderly patients that have heart disease or Parkinson's disease, we could take a little cell from their body they'd never miss and sort of take the cell back in time and recreate young cells and tissues that could be used for treating disease. ALDA: A tiny electric shock will stimulate the adult skin cell to start dividing. Somehow the environment of the egg leads the adult cell to behave like it's young, and begin to make embryonic stem cells. They've tried this with both cow and human eggs, so far with partial success. The number of divisions the implanted adult cell has made has been limited, but it's a start. WEST: The magic is, it's possible to make this sort of mother of all stem cells, the embryonic stem cell that's genetically identical to you, so that you... So I won't reject it, huh? If you make me a new organ or make me, uh... anything I might need because of the disease I have, I won't reject it. It's not coming from another person or another animal. The big unsolved problem, the reason thousands of people die every day, is the lack of transplantable cells and tissues that your body will not reject. And this new technology could be the long-sought means of transplanting cells and tissues that your body will not reject. ALDA: Back at the Langer Lab, they're working on the assumption that human stem cells of all kinds will eventually be available-- eye cells, for example. We're trying to create scaffolds that have pore sizes as low as ten microns on the way up to a millimeter. How small are you talking here? A micron is... What relationship is a micron to a human hair, for instance? Right, so a human hair is about 200 microns approximately. This is extremely tiny. How do you keep track of what you're doing? How do you actually build things that small? ALDA: Erin Lavick is going to teach me how to make a polymer scaffold like the ones used to build the heart tissue and the nose. But my scaffold is going to have the right fine pore structure to repair a damaged retina. LAVICK: This is the polymer dissolved in a solvent. ALDA: So this is what this scaffolding will be made of. Right. You're going to squirt it onto the slide. All of it? Mm-hmm. And then what you're going do is you're just going take that slide and slide it into the water. Oh, there's water there? Yep. Slide it into the water. Yeah, just like that. And so what's happening is when you slide it into the water, all of the solvent starts to come out and go into the water, and that transfers what's creating the pore structure in this case. ALDA: Erin's made thousands of these scaffolds, gradually refining her methods. LAVICK: These are some of the scaffolds that we've made using this technique, and these have all been dried. And so what you can see is they're very thin. You don't want to put something bulky in back of a retina. This looks like a piece of paper. But if you look at it under a scanning electron microscope, it actually has pores. ALDA: The tiny pores, each about 1/20 the thickness of a hair, are channels made by the solvent when it flowed out of the polymer. Next, working with Erin's colleague, Michael Young, I'm going to seed the scaffold with retinal stem cells. Now, I put... Just on... right in the middle of that big polymer. Just a little drop. Yeah, you can use all of that. That should be fine. And that's it. So I've seeded a polymer with stem cells. Yes. ALDA: Now we're going to see how the cells like it inside the scaffold. We're working with mouse retinal stem cells collected from a newborn animal as the eye was developing, so they're already on track to become part of the eye. Human cells like this aren't yet available. Okay... What are we looking at here? So this is the same type of polymer that we just looked at and seeded except I did it yesterday. You can see the pores in the polymer, if I focus. Yeah. But you can't see any cells, okay, because they're very small. ALDA: But when we shine an ultraviolet light on the cells, they burst into life. Now we can see retinal stem cells. ALDA: The cells have been modified to produce a fluorescent material as part of their normal life processes, so bright green spots mean healthy cells. This is beginning to look like a living retina. We're going to see what Michael and Erin are doing with the artificial retina, but first take a look at a normal eye. The retina's at the back. It has a thin cover of nerve cells on top of a thick layer of light-sensitive photoreceptor cells. They react whenever light is focused on them. In one of the first tests, the artificial retina was placed alongside a retina from a special breed of lab animal that has no thick layer of light-sensitive cells. ALDA: So, this layer, these channels-- that's that polymer I made in the dish on the slide. LAVICK: Mm-hmm, right. And now you're looking at it sideways, and these are the pores that the cells are growing in? Right, the darker parts are where the polymer actually is, and then these lighter parts here are actually the pores themselves. ALDA: Here you can see the living retinal cells sheltering inside the artificial retina. This was done just in a dish on the lab bench, but now here's the next step. This is a shot looking into the animal's eye. There at the back you can see the faint shape of the artificial retina, now implanted. Here's the same shot in ultraviolet light, showing that the cells in the implant are alive and healthy. What the researchers think is happening is that the retinal stem cells inside the implant are forming new light-sensitive photoreceptor cells which connect to the existing nerve cells in the animal's eye. It's still too early to tell if there's an actual improvement in vision, but it's a big step nonetheless. ALDA: If you're starting with a retinal stem cell, does that mean it has some properties that already predispose it to becoming a photoreceptor? YOUNG: Exactly, that's what we hope. But it's all... it could become some other part of the eye... Yes. If... if it were placed someplace else or under other conditions? What makes it become a photoreceptor when... when you do this... this procedure? One of the things that we've kind of hit upon is that the host actually instructs the cells at some level. So if we put these cells into an animal who has lost photoreceptors, the majority of these cells actually become photoreceptors. So the injury cue we think is critical. The injury itself somehow creates a cue for the growth of new cells. Now, it's interesting because that sounds like the body is signaling itself and trying to grow new cells. Exactly. But it's only when you supply the... the raw material that the body, for some reason, is lacking... Right. Or is being inhibited from presenting. Exactly. What's... what's going on here? I think... I think that's... So if you look at lower animals-- frogs, for instance, some fish-- they can grow a whole new retina. You take out the retina, they can grow a new one, even in an adult. We've lost that ability. But what we think is still present are some of these injury cues. So maybe these instructions for fixing the retina are actually there, but in higher mammals, for instance, we are simply unable to respond to that. So we're taking advantage, we hope, of these cues that are present and, as you say, adding the raw materials to fix what's wrong. So the cues that are happening could be vestigial mechanisms, vestigial functions... Right. That are useless to us because we've evolved away from them, but you can pick up on them and make use of them. What a fascinating... I mean, if... The cells can. We don't actually know what these injury cues are, but we know... we know they're present. ALDA: If there's a secret to the new science of bioengineering, this is it: If we just provide the right conditions, stem cells will do their thing. We don't have to know everything about how complex cellular systems work. So we may be glimpsing a future with almost limitless possibilities for repairing or replacing body parts. In our next story, we'll meet the scientist who wants to put together a whole system of body parts, functioning like a body, on the lab bench. The sample is in the vacuum chamber. It's like a superhigh vacuum.

				Body on a Bench A tiny, living liver is the first step towards a lab version of the human body.
		Select text to jump ahead in the clip: ALDA: How long have you been...? ALDA: This story is about something called a "liver chip." Three years, three years. Three years? Yeah, and we've actually got it there, so... And it's not just chipped liver. ALDA: You know, at MIT you don't expect a lot of jokes. ( laughing ) You'll see. Oh, "chipped liver," I get it. That's a joke-- I get it. It's a science... a liver science joke. That's even better. Do you make them in here? Yeah, we make them right over here. ALDA: Linda Griffith is a bioengineer who's developing a tiny bioreactor that behaves like a liver. So, Karel, you got everything all ready to set one up? Hi. How are you? DOMANSKY: So, we have a miniature bioreactor here. ALDA: It's called a liver chip because it uses thin, perforated wafers of silicon-- the same material computer chips are made with. Here they use silicon not for its electrical properties, but because we know a lot about making tiny structures with it. Once the chip is sealed in its case, a broth of about a dozen different nutrients and vitamins is pumped through the perforations. Then comes the final step, the one that turns a chip into a liver chip. So now... this is the room where we do all of our cell culture. And so these are sterile cell culture hoods and incubators for the cells. And Anand is now introducing the cells into the sterile bioreactor. ALDA: As with the artificial retina, they seed the chip with stem cells. These cells are already on track to develop into liver. As the chip is incubated over the next few days, the cells will take up residence in the chip's perforations. It's like having a colony of livers living in the lab, and that's kind of how the researchers feel about it. ALDA: How do you keep track? Do you give them little names or...? They do give them little names which I find out when I get the file for a publication or a presentation. It'll have "Here's the data from 'Mandy,' and 'Mandy' was very good, but 'Tom' was really not." ( laughing ) ALDA: But now you can work with "Tom" and "Mandy." You can test drugs or do experiments that would be out of the question with people. ALDA: Why did you make a small liver instead of a small heart or a small kidney? Well, partly just by chance. I happened to join a lab that was interested in liver and I got fascinated by the problems in liver. Liver is your largest organ. It gets almost a third of the blood flow every time your heart pumps. Liver does an amazing number of things. It detoxifies drugs. It keeps track of all the nutrients in your body to make sure the rest of your body gets exposed to almost constant amounts of glucose. It makes almost all the proteins found in your plasma. It synthesizes bile. It... it does so many things and it's so important so that when your liver gets sick, you have to replace it with an organ transplant or you die. And so it's such an essential organ. We got very interested in ways that we could... My first interest was in how we could do replacement livers to implant into people. What we realize now is that, gee, if we understood how liver works better and how disease processes go on in liver, we could develop better drugs and prevent the need for organ transplants in a lot of cases, we hope. Now, why... why do you need this to develop better drugs? Why can't you use... cells from a liver in a dish? Well, cells from a liver in a dish will do some of the things that liver does. But it's been really frustrating for years, and hundreds of people at all kinds of labs and industries have tried to get liver to do things like be infected with hepatitis virus. And when you take liver cells out of the body, they just go, "On strike-- I'm not doing all those things anymore." ALDA: Inside the liver chip, the cells are able to behave much more naturally. We moved over to the electron microscope to take a look. So the... the sample is in the vacuum chamber being bombarded with electrons. ALDA: First, here's how nature makes a liver. And what's this a picture of? This right now is actually a picture of a section of real liver. ALDA: Real liver contains thousands of tiny blood vessels like this, bringing in and taking away the many different chemicals which the liver cells off to the sides are processing. TECHNICIAN: This is a blood vessel that you're looking down into, so it's a cross section of a blood vessel. And they have small holes that sort of act as a filter to the blood. So the blood moves through here, and small molecules can go through and come in direct contact with the liver-functioning cells. ALDA: Without these tissue structures of filter holes and blood vessels, it's tough for the liver cells to function correctly. Now let's look at the liver chip. TECHNICIAN: So we're looking down on the chip and each of these channels is sort of like a tunnel where the medium can flow through, and there's a tissue structure that goes into the channel. So now I'll zoom in closer into one of these channels so that you can see what the tissue looks like. ALDA: The fascinating thing is that the stem cells in the chip grow into structures with many of the key features of real liver. They build channels like blood vessels inside each perforation in the chip, and they even make the little filter holes that real liver blood vessels have. What makes it organize itself as though it were in a real liver with these... with these spaces for the blood? Well, the environment that the cells are in makes them want to function in the way they do in the body so that they reorganize into structures that are like in the body. GRIFFITH: It's the Colonel's special recipe that we have in our secret vault at MIT. ALDA: And that's not just another of Linda's science jokes. There is a special recipe. The chip was designed specifically to keep liver cells happy-- the right size channels, the right nutrient flows, and surface coatings they like to stick to. Linda believes we can do this for many body parts. You know, when you show me these pictures that are enlarged so much, and you were looking at these almost infinitesimally small places in the body, and you say things like, "And they open and close depending on various things," or... or these little parts of the cell, or cells are in communication with other cells or sending out... GRIFFITH: Mm-hmm. It sounds like there are so many millions or billions of things going on in the body-- signals being sent, coming back, sending out, going out again. Is there a hope that we'll be able to untangle this puzzle, I mean, in anybody's lifetime? GRIFFITH: Yes. We started a whole new department, actually, at MIT to address exactly these kinds of problems-- biological engineering-- and bringing together biologists and engineers and really trying to do systems-level biology starting at the molecular level. So it's just really starting to creep out across universities in America, but I... I think it'll happen. ALDA: Making body parts like retinas or livers in the lab depends critically on acquiring the right human stem cells, not the animal cells they're using here right now. One of the biggest hurdles in this is where we're going to ultimately get the cells to do it on a large scale. And so part of our project actually is to try to derive stem cell lines that can be cultured and frozen down out of human tissue. Are these stem cell lines that you're talking about creating here... are they outside of the... the prohibitions placed on stem cell research recently by Washington or are they within those protocols? What we are doing is taking cells out of the adult body and trying to derive cell lines, so they're not under the prohibitions. They're much more readily available to the general researcher. We can even get some from you if you sign the consent form. We'll have the memorial cell line. We'll... we'll talk later about that. ( laughing ) Do you ask most people who come in if they want to give up their stem cells? Um... if we really like them and we want to have them memorialized in the lab. Gee, you mean I could come someday and visit my cells? You could, yeah. Gee, that would be great. I could maybe have my own chip here. You know, you could maybe have your whole body on a chip. You know, if what we're doing really works out, we could take stem cells that circulate in your blood and make a liver, make a heart, make a brain out of those cells. That's our ultimate goal. That's what I want to have done by the time I retire from MIT.

				Search for the Perfect Heart Science continues the quest to replace our most critical organ. (Updated from earlier broadcasts)
		Select text to jump ahead in the clip: ALDA: On July 4, 2001, the papers announced a new kind of independence for heart patients, available now for the first time. The implantable self-contained mechanical heart was the culmination of at least 40 years of research. On Frontiers, we've been following its progress for almost ten years. In 1993, we told the story of Mike Dorsey, whose life was saved by a sort of partial artificial heart, called a HeartMate, that assisted his own failing heart. DORSEY: I was very sick. If I'd have walked from here to you, I'd been out of breath for that time. You know, I couldn't do nothing. It gets a little frustrating when your wife comes and takes things from you, you know, and you can't carry them, you know. She would take them and carry them in for me. I wanted to do it but just wasn't able to do it. ALDA: The artificial heart first hit the world's headlines in 1982. Barney Clark's brave struggle to live and his death after four months cooled the early enthusiasm for his implant, the Jarvik-7. After a few more unsuccessful attempts, the device was abandoned. But research on mechanical hearts continued. The most promising were pumps that weren't intended to replace the heart but boost it, like Mike Dorsey's HeartMate. ( pump chugging rhythmically ) The designers of the HeartMate took a novel approach to a major problem of the Jarvik-7-- blood clots that would form inside it and that could kill when they broke off and traveled to the lungs or brain. The HeartMate's interior was roughened so that a thin layer of blood clots over its entire surface and sticks there firmly. Mike Dorsey's problem, one that he shares with thousands of others each year, was a weakening of his heart muscle so that the main pumping chamber, the left ventricle, could no longer pump blood around his body. Installing the HeartMate begins with cutting a hole in the left ventricle and sewing in a short tube. Then the electric pump itself is implanted in the upper abdomen. Blood flows from the heart through the pump, then back to the patient's aorta. By February 1993, Mike Dorsey's heart was near total failure. His doctors estimated he had just hours to live. Only weeks before, the HeartMate had been approved by the Food and Drug Administration for use at Fairfax Hospital in Virginia to keep a dying patient alive until a heart transplant could be found. ( heart monitor beeping, surgical team speaking softly ) The operation began with sewing into Mike's left ventricle the tube that connected with the pump. Then the HeartMate itself was slid into place. The connection was made between the pump and the heart it would assist. ( monitors beeping ) Finally, the pump's outflow tube was plumbed into Mike's aorta. The pump was switched on. And at this point, no one knew for how long it would need to keep pumping. The HeartMate needed an awkward external battery-powered air pump with an air tube penetrating the skin. It was only intended to be a temporary bridge, to keep the patient alive until a transplant heart became available. After seven months, Mike was still waiting, confined to the hospital. DORSEY: It's not really me. I'd rather be moving where I have a destination to go to instead of standing in one spot looking at the same old scenery. This is the battery charger here. In order to be more mobile, take two batteries, these... and just connect the power source from here. ( shrill alarm sounds ) ALDA: That's the alarm that went off if there was ever a problem. You don't do it right, they do not go. And just drop them into the pouch like this, fold the flap down. Now I'm ready for traveling. ALDA: Mike got his transplant a few weeks after this, and today he's still going strong. Hi, Michael. ALDA: But now we're much closer to being able to offer patients like Mike a permanently implanted artificial heart. About 125,000 of the 700,000 Americans who die from heart failure each year could benefit from an artificial implant. The Abiomed artificial heart is modeled on the human, with two main pumping chambers and valves to control blood flow. ALDA: As the blood goes through there, it pushes its way through, but it can't come back the other way, right? MAN: Correct. ALDA: Can that be relied on after it pumps thousands of times, after... if you pass through... after it flexes thousands of times, to maintain that same resiliency? The answer is yes, and it's not thousands of times, it's approximately 100,000 times per day. ( laughing ): Oh, boy. Which is close to 40 million times per year. 40 million times. You can flex this material 40 million times, and... Without it breaking. Without it... not only breaking, but just weakening and softening and fluttering and that kind of thing? Correct. So, this is where you test the valves. Yes, this is where we test. We have many, many valves under test. And we test them under very severe conditions and at an accelerated rate so that we can demonstrate 20 years' equivalency in one year. ALDA: Just like the HeartMate, the Abiomed heart is designed to avoid the danger of blood clots forming inside it. But while the HeartMate has a deliberately roughened interior surface, the Abiomed heart aims to be completely smooth and seamless. It also keeps the blood constantly swirling-- made visible here with fish scales in water-- to minimize stagnant areas where clots might form. ( water sloshing ) It's not until I get to hold the heart while it's pumping that I really appreciate how powerful it has to be to substitute for a human heart. ( pump rhythmically slurping ) I can really feel the beating. Now interestingly, when you see a heart pumping, the outside of the heart is going like that, you see the motion on the outside. Here all the motion is inside this device. ( water sloshing ) I've held on to this heart long enough. Would you mind holding that for a day or two? ALDA: The Abiomed heart is run by rechargeable batteries that receive their power through the skin. Both Mike Dorsey's HeartMate and Barney Clark's Jarvik-7