All Pumped Up: Team Creates a Beating Rat Heart
by Rebecca Hirsch | Today's Science, February 2008
© 2008 Today's Science
When Doris Taylor set out to create a beating heart in her laboratory, she realized what she was up against.
"The heart is a beautiful, complex organ," Taylor told National Public Radio's All Things Considered. "We realized pretty quickly that we weren't going to be able to figure out how to build that in a dish."
But that didn't stop her from following her mantra to "trust your crazy ideas." Turns out, those crazy ideas have served her well. She and her colleagues at the University of Minnesota in Minneapolis have created the world's first laboratory-made, beating rat heart. The team reported their results online in the journal Nature Medicine.
That accomplishment brings doctors and scientists several steps closer to fulfilling one of the great hopes of modern medicine: being able to grow hearts and other organs in the laboratory for transplant into patients whose own organs are failing.
No Longer Young at Heart
Worldwide, 22 million people live with heart failure. The condition happens when the heart—weakened by a defect, damaged by abuse, or ravaged by disease—becomes too weak to pump all the blood the body needs. Other organs, deprived of oxygen, also may fail. Feet and legs swell. Lungs fill with liquid. The patient feels tired and short of breath, unable to tolerate even light exercise.
A heart transplant may be the one hope left for people with severe heart failure. Problem is, hearts are scarce. On any given day, over 3,000 heart patients in the U.S. are waiting for a transplant. For every patient lucky enough to receive a heart, many more will die waiting.
Medical researchers have long dreamed of growing hearts in the laboratory as a way to remedy the shortage. It is not difficult to grow heart cells or tissue in a petri dish. What is tricky is coaxing those cells to grow into a complex, three-dimensional organ.
"Nature has done a great job making these organs," Taylor told Talk of the Nation. "And it became really clear to us we couldn't build one. We weren't smart enough or didn't understand it well enough. So we just took the simple approach: let's let nature do it for us."
Taylor's team thought they might have success if they used the same approach nature takes, which is to build the new heart over an existing frame or scaffold. In nature that scaffold is mostly made of proteins. The team hypothesized they could make a frame similar to the one nature uses if they removed the cells from a dead heart. Strip the cells away, and what is left is the extracellular matrix, the protein-rich meshwork that holds the organ together.
"You can think of it as the bare wooden frame for a house," Taylor said.
Great idea, but would it work? The time had come to test whether cells could build a new heart using an old one as scaffolding.
Washing the Cells Away
Taylor gave the assignment to Harold Ott, then a graduate student in her lab. Ott took it on as a side project. His first hurdle was to figure out how to decellularize the heart, or strip the old cells away.
"We had a big chemical shelf in the lab, from A to Z," Ott told All Things Considered. "So I started using all sorts of chemicals starting at A."
Ott performed the experiments on hearts taken from rat cadavers. Some chemicals made the heart swell. Other dissolved the entire organ, proteins and all. Then one day, Ott came to a chemical on the shelf called sodium dodecyl sulfate, SDS for short. As far as laboratory chemicals go, SDS is pretty run of the mill. It is a detergent, commonly added to give sudsy lather to shampoos, shaving cream, toothpaste and dish soap. (You will usually find SDS listed as an ingredient in such products under its other name, sodium lauryl sulfate.)
SDS turned out to be the magic ingredient. Bathed in SDS and water, over several hours the dead red heart slowly turned white. Its cells were being stripped away. The protein meshwork remained behind, leaving the heart with its complex internal structure intact.
"You can see the detergent working and making the heart literally translucent so it turns into a jellyfish sort of appearance," Ott told All Things Considered.
Ott then washed away the soap solution and soaked the old heart in a bath of nutrients. He injected new heart cells, taken from a newborn baby rat. The cells took hold and started to grow. Soon the heart turned red again.
The structure now looked like a heart, but it wouldn't beat. So the team hooked it up to a pacemaker. Soon the heart began to show signs of life.
"When we saw the first heartbeats, we were speechless," Ott said.
The research sounds rather straightforward now, but Taylor admits that progress on the new technique was slow. "We made every mistake known, did every experiment wrong and had to go back and do them right," she told The New York Times.
Moving from Rats to Pigs and Humans
Other researchers called the advance exciting. Speaking to The New York Times, Todd N. McAllister of Cytograft Tissue Engineering in Novato, California, said it was "one of those maddeningly simple ideas that you knock yourself on the head, saying, 'Why didn't I think of that?' "
Taylor said, "It's time to move forward and see if we can make a difference in the lives of people with disease."
First she needs to improve the technique. The hearts in the first round of engineered rat hearts weren't very strong. They pumped with only 2% of the efficiency of an adult rat heart. Taylor wants to improve on that.
"We only let it go for a couple of weeks and we didn't try to make it strong enough. So our hope now is that it's really a matter of adding more cells and letting it go longer and we're on the way," she told Talk of the Nation.
"The really encouraging thing for us is that we think we've made a step forward in maybe creating a heart that can be used for transplant one day," she said.
Toward that goal, Taylor's team is trying the approach on human-sized pig hearts. She imagines that doctors may someday be able to custom order hearts for their patients. A pig heart or unusable human heart would be stripped down to its frame and reseeded with the patient's own cells.
The idea is not that far-fetched. Doctors already transplant decellularized pig valves into humans. Over time, the protein framework gets replaced with the patient's proteins. Once the framework consists entirely of the patient's own proteins, the patient may not need the usual anti-rejection drugs.
Taylor and others cautioned that such an advance in transplant therapy is likely to be at least 10 years off. Many hurdles must be overcome, not the least of which is finding cells that are good at re-forming old hearts.
The approach may also prove useful on other organs. Taylor's team has already achieved success in making scaffolds for lungs, livers and kidneys.
Ott, who now works as a physician at Massachusetts General Hospital, said, "I see a drastic need for more donor organs by simply working in a hospital setting on an everyday basis. If our research becomes applicable to humans, which we think it may, it has the potential to save millions of lives."
"We're not there yet," Taylor said, "but this is a good first step."
© 2008 Today's Science
When Doris Taylor set out to create a beating heart in her laboratory, she realized what she was up against.
"The heart is a beautiful, complex organ," Taylor told National Public Radio's All Things Considered. "We realized pretty quickly that we weren't going to be able to figure out how to build that in a dish."
But that didn't stop her from following her mantra to "trust your crazy ideas." Turns out, those crazy ideas have served her well. She and her colleagues at the University of Minnesota in Minneapolis have created the world's first laboratory-made, beating rat heart. The team reported their results online in the journal Nature Medicine.
That accomplishment brings doctors and scientists several steps closer to fulfilling one of the great hopes of modern medicine: being able to grow hearts and other organs in the laboratory for transplant into patients whose own organs are failing.
No Longer Young at Heart
Worldwide, 22 million people live with heart failure. The condition happens when the heart—weakened by a defect, damaged by abuse, or ravaged by disease—becomes too weak to pump all the blood the body needs. Other organs, deprived of oxygen, also may fail. Feet and legs swell. Lungs fill with liquid. The patient feels tired and short of breath, unable to tolerate even light exercise.
A heart transplant may be the one hope left for people with severe heart failure. Problem is, hearts are scarce. On any given day, over 3,000 heart patients in the U.S. are waiting for a transplant. For every patient lucky enough to receive a heart, many more will die waiting.
Medical researchers have long dreamed of growing hearts in the laboratory as a way to remedy the shortage. It is not difficult to grow heart cells or tissue in a petri dish. What is tricky is coaxing those cells to grow into a complex, three-dimensional organ.
"Nature has done a great job making these organs," Taylor told Talk of the Nation. "And it became really clear to us we couldn't build one. We weren't smart enough or didn't understand it well enough. So we just took the simple approach: let's let nature do it for us."
Taylor's team thought they might have success if they used the same approach nature takes, which is to build the new heart over an existing frame or scaffold. In nature that scaffold is mostly made of proteins. The team hypothesized they could make a frame similar to the one nature uses if they removed the cells from a dead heart. Strip the cells away, and what is left is the extracellular matrix, the protein-rich meshwork that holds the organ together.
"You can think of it as the bare wooden frame for a house," Taylor said.
Great idea, but would it work? The time had come to test whether cells could build a new heart using an old one as scaffolding.
Washing the Cells Away
Taylor gave the assignment to Harold Ott, then a graduate student in her lab. Ott took it on as a side project. His first hurdle was to figure out how to decellularize the heart, or strip the old cells away.
"We had a big chemical shelf in the lab, from A to Z," Ott told All Things Considered. "So I started using all sorts of chemicals starting at A."
Ott performed the experiments on hearts taken from rat cadavers. Some chemicals made the heart swell. Other dissolved the entire organ, proteins and all. Then one day, Ott came to a chemical on the shelf called sodium dodecyl sulfate, SDS for short. As far as laboratory chemicals go, SDS is pretty run of the mill. It is a detergent, commonly added to give sudsy lather to shampoos, shaving cream, toothpaste and dish soap. (You will usually find SDS listed as an ingredient in such products under its other name, sodium lauryl sulfate.)
SDS turned out to be the magic ingredient. Bathed in SDS and water, over several hours the dead red heart slowly turned white. Its cells were being stripped away. The protein meshwork remained behind, leaving the heart with its complex internal structure intact.
"You can see the detergent working and making the heart literally translucent so it turns into a jellyfish sort of appearance," Ott told All Things Considered.
Ott then washed away the soap solution and soaked the old heart in a bath of nutrients. He injected new heart cells, taken from a newborn baby rat. The cells took hold and started to grow. Soon the heart turned red again.
The structure now looked like a heart, but it wouldn't beat. So the team hooked it up to a pacemaker. Soon the heart began to show signs of life.
"When we saw the first heartbeats, we were speechless," Ott said.
The research sounds rather straightforward now, but Taylor admits that progress on the new technique was slow. "We made every mistake known, did every experiment wrong and had to go back and do them right," she told The New York Times.
Moving from Rats to Pigs and Humans
Other researchers called the advance exciting. Speaking to The New York Times, Todd N. McAllister of Cytograft Tissue Engineering in Novato, California, said it was "one of those maddeningly simple ideas that you knock yourself on the head, saying, 'Why didn't I think of that?' "
Taylor said, "It's time to move forward and see if we can make a difference in the lives of people with disease."
First she needs to improve the technique. The hearts in the first round of engineered rat hearts weren't very strong. They pumped with only 2% of the efficiency of an adult rat heart. Taylor wants to improve on that.
"We only let it go for a couple of weeks and we didn't try to make it strong enough. So our hope now is that it's really a matter of adding more cells and letting it go longer and we're on the way," she told Talk of the Nation.
"The really encouraging thing for us is that we think we've made a step forward in maybe creating a heart that can be used for transplant one day," she said.
Toward that goal, Taylor's team is trying the approach on human-sized pig hearts. She imagines that doctors may someday be able to custom order hearts for their patients. A pig heart or unusable human heart would be stripped down to its frame and reseeded with the patient's own cells.
The idea is not that far-fetched. Doctors already transplant decellularized pig valves into humans. Over time, the protein framework gets replaced with the patient's proteins. Once the framework consists entirely of the patient's own proteins, the patient may not need the usual anti-rejection drugs.
Taylor and others cautioned that such an advance in transplant therapy is likely to be at least 10 years off. Many hurdles must be overcome, not the least of which is finding cells that are good at re-forming old hearts.
The approach may also prove useful on other organs. Taylor's team has already achieved success in making scaffolds for lungs, livers and kidneys.
Ott, who now works as a physician at Massachusetts General Hospital, said, "I see a drastic need for more donor organs by simply working in a hospital setting on an everyday basis. If our research becomes applicable to humans, which we think it may, it has the potential to save millions of lives."
"We're not there yet," Taylor said, "but this is a good first step."
