Monthly Archives: June 2013

To ease shortage of organs, grow them in a lab?

By the time 10-year-old Sarah Murnaghan finally got a lung transplant last week, she’d been waiting for months, and her parents had sued to give her a better shot at surgery.

Her cystic fibrosis was threatening her life, and her case spurred a debate on how to allocate donor organs. Lungs and other organs for transplant are scarce.

But what if there were another way? What if you could grow a custom-made organ in a lab? polymer-scaffold-1s

It sounds incredible. But just a three-hour drive from the Philadelphia hospital where Sarah got her transplant, another little girl is benefiting from just that sort of technology. Two years ago, Angela Irizarry of Lewisburg, Pa., needed a crucial blood vessel. Researchers built her one in a laboratory, using cells from her own bone marrow. Today the 5-year-old sings, dances and dreams of becoming a firefighter — and a doctor.

Growing lungs and other organs for transplant is still in the future, but scientists are working toward that goal. In North Carolina, a 3-D printer builds prototype kidneys. In several labs, scientists study how to build on the internal scaffolding of hearts, lungs, livers and kidneys of people and pigs to make custom-made implants.

Here’s the dream scenario: A patient donates cells, either from a biopsy or maybe just a blood draw. A lab uses them, or cells made from them, to seed onto a scaffold that’s shaped like the organ he needs. Then, says Dr. Harald Ott of Massachusetts General Hospital, “we can regenerate an organ that will not be rejected (and can be) grown on demand and transplanted surgically, similar to a donor organ.”

That won’t happen anytime soon for solid organs like lungs or livers. But as Angela Irizarry’s case shows, simpler body parts are already being used as researchers explore the possibilities of the field.

Just a few weeks ago, a girl in Peoria, Ill., got an experimental windpipe that used a synthetic scaffold covered in stem cells from her own bone marrow. More than a dozen patients have had similar operations.

Dozens of people are thriving with experimental bladders made from their own cells, as are more than a dozen who have urethras made from their own bladder tissue. A Swedish girl who got a vein made with her marrow cells to bypass a liver vein blockage in 2011 is still doing well, her surgeon says.

In some cases the idea has even become standard practice. Surgeons can use a patient’s own cells, processed in a lab, to repair cartilage in the knee. Burn victims are treated with lab-grown skin.

In 2011, it was Angela Irizarry’s turn to wade into the field of tissue engineering.

Angela was born in 2007 with a heart that had only one functional pumping chamber, a potentially lethal condition that leaves the body short of oxygen. Standard treatment involves a series of operations, the last of which implants a blood vessel near the heart to connect a vein to an artery, which effectively rearranges the organ’s plumbing.

Yale University surgeons told Angela’s parents they could try to create that conduit with bone marrow cells. It had already worked for a series of patients in Japan, but Angela would be the first participant in an American study.

“There was a risk,” recalled Angela’s mother, Claudia Irizarry. But she and her husband liked the idea that the implant would grow along with Angela, so that it wouldn’t have to be replaced later.

So, over 12 hours one day, doctors took bone marrow from Angela and extracted certain cells, seeded them onto a 5-inch-long biodegradable tube, incubated them for two hours, and then implanted the graft into Angela to grow into a blood vessel.

It’s been almost two years and Angela is doing well, her mother says. Before the surgery she couldn’t run or play without getting tired and turning blue from lack of oxygen, she said. Now, “she is able to have a normal play day.”

This seed-and-scaffold approach to creating a body part is not as simple as seeding a lawn. In fact, the researchers in charge of Angela’s study had been putting the lab-made blood vessels into people for nearly a decade in Japan before they realized that they were completely wrong in their understanding of what was happening inside the body.

“We’d always assumed we were making blood vessels from the cells we were seeding onto the graft,” said Dr. Christopher Breuer, now at Nationwide Children’s Hospital in Columbus, Ohio. But then studies in mice showed that in fact, the building blocks were cells that migrated in from other blood vessels. The seeded cells actually died off quickly. “We in essence found out we had done the right thing for the wrong reasons,” Breuer said.

Other kinds of implants have also shown that the seeded cells can act as beacons that summon cells from the recipient’s body, said William Wagner, director of the McGowan Institute for Regenerative Medicine at the University of Pittsburgh. Sometimes that works out fine, but other times it can lead to scarring or inflammation instead, he said. Controlling what happens when an engineered implant interacts with the body is a key challenge, he said.

So far, the lab-grown parts implanted in people have involved fairly simple structures — basically sheets, tubes and hollow containers, notes Anthony Atala of Wake Forest University whose lab also has made scaffolds for noses and ears. Solid internal organs like livers, hearts and kidneys are far more complex to make.

His pioneering lab at Wake Forest is using a 3-D printer to make miniature prototype kidneys, some as small as a half dollar, and other structures for research. Instead of depositing ink, the printer puts down a gel-like biodegradable scaffold plus a mixture of cells to build a kidney layer by layer. Atala expects it will take many years before printed organs find their way into patients.

Another organ-building strategy used by Atala and maybe half a dozen other labs starts with an organ, washes its cells off the inert scaffolding that holds cells together, and then plants that scaffolding with new cells.

“It’s almost like taking an apartment building, moving everybody out … and then really trying to repopulate that apartment building with different cells,” says Dr. John LaMattina of the University of Maryland School of Medicine. He’s using the approach to build livers. It’s the repopulating part that’s the most challenging, he adds.

One goal of that process is humanizing pig organs for transplant, by replacing their cells with human ones.

“I believe the future is … a pig matrix covered with your own cells,” says Doris Taylor of the Texas Heart Institute in Houston. She reported creating a rudimentary beating rat heart in 2008 with the cell-replacement technique and is now applying it to a variety of organs.

Ott’s lab and the Yale lab of Laura Niklason have used the cell-replacement process to make rat lungs that worked temporarily in those rodents. Now they’re thinking bigger, working with pig and human lung scaffolds in the lab. A human lung scaffold, Niklason notes, feels like a handful of Jell-O.

Cell replacement has also worked for kidneys. Ott recently reported that lab-made kidneys in rats didn’t perform as well as regular kidneys. But, he said, just a “good enough organ” could get somebody off dialysis. He has just started testing the approach with transplants in pigs.

Ott is also working to grow human cells on human and pig heart scaffolds for study in the laboratory.

There are plenty of challenges with this organ-building approach. One is getting the right cells to build the organ. Cells from the patient’s own organ might not be available or usable. So Niklason and others are exploring genetic reprogramming so that, say, blood or skin cells could be turned into appropriate cells for organ-growing.

Others look to stem cells from bone marrow or body fat that could be nudged into becoming the right kinds of cells for particular organs. In the near term, organs might instead be built with donor cells stored in a lab, and the organ recipient would still need anti-rejection drugs.

How long until doctors start testing solid organs in people? Ott hopes to see human studies on some lab-grown organ in five to 10 years. Wagner calls that very optimistic and thinks 15 to 20 years is more realistic. Niklason also forecasts two decades for the first human study of a lung that will work long-term.

But LaMattina figures five to 10 years might be about right for human studies of his specialty, the liver.

“I’m an optimist,” he adds. “You have to be an optimist in this job.”


Source: AP, Malcolm Ritter, Michael Rubinkam, Allen breed


Mayo Clinc puts stem cells to the test on infant heart defect

Every year, about 1,000 babies are born in the United States with half a heart — a rare defect that requires a series of risky surgeries and, even then, leaves the infants with a strong likelihood that their hearts will wear out prematurely. heart_525

Now, the Mayo Clinic has received federal approval for a first-of-its kind clinical study to see if stem cells from the babies’ own umbilical cords can strengthen their underdeveloped hearts and extend their lives.

If it works, the new technique could buy these children time as scientists scramble for a cure for the congenital defect called hypoplastic left heart syndrome (HLHS).

The Mayo study, which will begin as soon as 10 eligible candidates can be enrolled, could also pave the way for additional breakthroughs in stem cell treatments that would help the 19,000 children born each year with other heart defects. But for the time being, the doctors at Mayo are keeping their focus on those babies who need the most help now.

“We are not here to build an academic career out of science and technology,’’ said Dr. Timothy Nelson, director of Mayo’s HLHS research program. “We’re really here to make a difference in children’s lives who are living today with unmet needs.”

Christina DeShaw of Clive, Iowa, was pregnant with fraternal twins when she learned during an ultrasound procedure that the left side of her daughter’s heart was not developing properly.

“The world just started spinning,” DeShaw said. “Our lives were forever changed from that moment on.”

DeShaw and her husband, Brad Weitl, sought help from the Mayo Clinic for the baby they named Ava Grace.

They learned that children born with defects on the left side of the heart must undergo a series of three complex surgeries. The first is called the Norwood procedure: Within a few days of birth, surgeons reconstruct the heart so that the fully developed right ventricle can do both its own work of supplying blood to the lungs and the work of the defective left ventricle, which ordinarily would pump oxygenated blood back to the body.

Dr. Harold Burkhart, who is overseeing surgeries in Mayo’s new study, said that when the procedure was developed in 1983, only about 30 percent of the patients survived. About 70 percent survive now, he said, and at Mayo, about 9 out of 10 make it through.

The second and third surgeries are much safer. They involve rerouting blood from the body directly to the lungs, bypassing the heart entirely to reduce the workload of the right ventricle.

Ava Grace Weitl was born by Caesarean section on May 8, 2012, then whisked away for her first surgery. “Her heart was the size of a walnut,” DeShaw said. “She had less than a 40 percent chance of making it.”

Ava remained under intensive care until Labor Day. DeShaw, who works at ING Financial Partners in Des Moines, spent months living in a Rochester hotel; her husband, a construction estimator, drove up on weekends. But their trauma didn’t stop when they finally took their daughter home. Ava has suffered numerous complications and once had to be flown back to Mayo in a helicopter.

Unfortunately, Ava won’t be eligible for the stem cell trial: The design calls for stem cells to be injected into the right ventricle during the second surgery, and Ava has already had hers.

Still, Ava’s parents remain dedicated to helping with Mayo’s research. “We wanted to participate, not only because we thought that at some point Ava might benefit, but we also wanted to help all the other babies … and to try to give them the best shot,’’ DeShaw said.

Seeds of life

Cardiac stem cell treatments were pioneered in adult patients. Worldwide, some 5,000 to 6,000 people have received stem cell treatments for heart conditions, but those procedures relied on cells taken from the patients’ bone marrow, said Dr. Atta Behfar, one of Mayo’s leading researchers in the field.

Behfar, working with Dr. Andre Terzic, a Mayo cardiovascular specialist, found that stem cells typically lose their vitality as they age and apparently become “sick” along with the patient. Mayo just finished a clinical trial in Europe showing that they could kick-start those cells in a way that significantly improves the patient’s health, cuts treatment costs and improves quality of life.

Nelson said he thinks stem cells taken from umbilical cord blood and placed into a growing heart will prove even more effective.

“I think of stem cells as seeds,” Nelson said. “If you plant that seed into a rocky, dry soil, that seed may not grow nearly as well as if you plant it into a black, rich, fertile soil that gets watered, irrigated and fertilized,” he said. “And so we think of this as planting these seeds into that fertile soil of a pediatric heart.”

Also, Nelson said, stem cells from the umbilical cord seem to know when to stop producing heart cells, so they don’t create the same cancer concerns that have been associated with the use of “pluripotent” embryonic cells or bioengineered cells in adult hearts.

Too few hearts

Nelson dedicated himself to finding a cure for hypoplastic left heart syndrome when he was studying to become a pediatric heart surgeon. He said it tore him up to know that babies who endured three open heart surgeries would often return as young children with irreparable heart damage and little likelihood of finding a donor heart in time to save them.

Some research suggested that half the children with HLHS don’t make it to their 5th birthday, Nelson said, but there are also children living into their early 20s. “So there are wonderful success stories of the surgical practice,” he said. “But obviously, the percentage of kids born that make it to that stage is far too low.”

Joshua and Sandra Hughes of Ashburn, Va., said they learned about Mayo’s pediatric heart research from a friend. Their 5-year-old daughter, Jaclyn, also has HLHS, and although she gets treated in Washington, D.C., they volunteered to participate in Mayo’s research program.

Jaclyn underwent an MRI last week, and she and her parents each contributed skin tissue for genetic testing and other research. Mayo’s Dr. Patrick O’Leary thanked them for spending two days in Rochester undergoing tests; he showed them images from Jaclyn’s scan and said her heart is performing quite well after her third surgery.

“The stuff they’re working on now may not be available for Jackie,” Sandra Hughes said. “But it may be available for the next generation.”

O’Leary interrupted her, voicing his optimism for the Mayo research.

“It may be available for her, too,” he said.


Source: Dan Browning, Star Tribune, Ashley Griffin, Kaiser Health

Stem Cells Reach Standard for Use in Drug Development

menschliche leber Drug development for a range of conditions could be improved with stem cell technology that helps doctors predict the safety and the effectiveness of potential treatments.

University scientists have been able to generate cells in the laboratory that reach the gold standard required by the pharmaceutical industry to test drug safety.

Generating liver cells

The researchers used stem cell technology to generate liver cells — which help our bodies to process drugs.

They found that the cells were equally effective, reaching the same standard, as cells from human liver tissue currently used to assess drug safety.

These human cells used in drug testing are in short supply and vary considerably due to different donors. As a result they are not an ideal source for drug development.

The stem cell based technique developed in Edinburgh, addresses these issues by offering a renewable production of uniform liver cells in the laboratory.

“Differing genetic information plays a key role in how patients’ livers process drugs. We are now able to efficiently produce human liver cells in the laboratory from different people which model the functional differences in human genetics,” said Dr David Hay, of the Medical Research Centre (MRC) for Regenerative Medicine at the University.

Researchers hope to generate liver cells, containing different DNA to reflect the genetic variations in metabolism found in the population

Such cells could be used to help identify differences in response among patients to certain drugs.

The laboratory-generated liver cells could also be used to screen certain drugs that need close monitoring, to optimise patient treatment.

Scientists are working with Edinburgh BioQuarter, with a view to forming a spin-out company to commercialise the research.


Source:, University of Edinburgh