Deepak Srivastava, director of the Gladstone Institute of Cardiovascular Disease, co-authored the new paper.

Reported for KQEDnews.org

Scientists at the Gladstone Institutes, a research foundation affiliated with the University of California-San Francisco, reported today that they have succeeded for the first time in creating beating heart cells from other types of adult cells.

The breakthrough offers new hope to the more than 5 million people in the United States who have survived heart attacks that one day their damaged hearts could be repaired.

When a person suffers a heart attack, the heart sustains damage than can permanently inhibit its function. Devices like pacemakers, and drugs like beta blockers, can keep the heart going, but not restore it to its full capacity – something that only a heart transplant can achieve today. But only about 2,000 hearts are available for transplants in the United States each year.

“This discovery opens a door to think about a different approach, which is to take cells that are already within a damaged heart and convert them from just a simple structural cell that’s not beating into a cell that’s beating like its neighbors,” said Dr. Deepak Srivastava, director of the Gladstone Institute of Cardiovascular Disease and a member of the research team.

“That can help the heart squeeze better and maybe avoid the need for transplantation.”

The new research appears in the August 6 edition of the journal Cell and was led by Masaki Ieda.

“It’s a major step forward in regenerative medicine,” said Dr. Ira Cohen, director of the Institute for Molecular Cardiology at Stony Brook University in New York, who wasn’t involved in the research. “It represents a novel approach to replacing heart cells.”

Research bypasses stem cells

The new research represents the first time that scientists have succeeded in creating beating heart muscle cells from adult cells that are not stem cells. Researchers had previously created heart muscle cells from both embryonic and adult stem cells.

Embryonic stem cells, and adult cells that have been made to act like embryonic stem cells, are referred to as being “pluripotent” because they have the unique ability to transform into many different types of cells. Scientists hope that one day stem cell research can lead to cures for a wide host of diseases, from diabetes to Parkinson’s. Stem cells that are pluripotent give researchers great flexibility, but they also could cause the wrong type of cell, or even a tumor, to end up in a patient’s heart. In bypassing stem cells, the new research avoids these potential problems, said Cohen.

The new research follows in the footsteps of a groundbreaking discovery by scientist Shinya Yamanaka, of the Gladstone Institutes and Kyoto University. In 2007, Yamanaka found that adult skin cells can be reprogrammed to become embryonic-like stem cells. Yamanaka and his team inserted four genes that are present in embryonic stem cells into adult cells. The four genes reprogrammed the adult cells to become embryonic-like stem cells.

The discovery, a major medical advance, offered a new way for stem cell research to proceed without many of the ethical and religious debates over the use of embryonic cells that had previously surrounded it.

And it also revealed to scientists that “in fact an adult cell could be induced to change so much, which we didn’t think was possible before,” said Srivastava.

Three genes did the trick

In the latest research, Srivastava and his team applied Yamanaka’s technique, but instead of seeking to create stem cells, they set out to bypass stem cells altogether. They took 15 genes from heart muscle cells and inserted them into adult cells called fibroblasts, which are found in the body’s connective tissue. They used fibroblasts from mice hearts and tails.

The researchers then looked for signs that the fibroblasts were becoming like heart muscle cells. Once they verified that heart muscle cells had been produced, they removed the genes one by one until they were left with the three genes that were necessary, but sufficient, to make the reprogramming happen.

The beating heart cells appear green.

Heart attacks are the number 1 cause of death in the United States, killing half a million people each year. This week’s research is an early step toward what one day could become a new treatment to repair the heart. Under one potential scenario, Srivastava said, rather than inserting genes into a patient’s heart, a doctor might deliver a therapeutic substance to the heart through a stent – without surgery – to transform non-beating heart cells into new beating heart cells.

To date, gene therapy has run into problems because introducing new genes into the human body can cause cancer.

One of the questions that the new research doesn’t answer is whether this technique would be able to generate enough heart muscle cells – which are called cardiomyocytes – to repair a damaged heart, said Cohen.

“You’re talking about replacing 1 billion cardiomyocytes,” he said. “How do you generate that many cells? How do you guarantee they’re healthy? How do you deliver them healthily? And how do you guarantee they stay there?”

Cardiac stem cells offer another possible treatment

Other approaches to regenerating heart cells also are being investigated.

Two clinical trials are underway in the United States to study the possibility of repairing the heart by giving patients an infusion of their own heart stem cells. Results of one of the trials, which is being carried out at the Cedars-Sinai Medical Center in Los Angeles, are due at the end of 2010, said researcher Rachel Smith, from the hospital’s Heart Institute.

In the so-called CADUCEUS trial, researchers take a few snips of the heart during an outpatient biopsy, then culture the tissue for three to four days to increase the number of stem cells. Close to 25 million cardiac stem cells are then infused into the heart through a catheter that goes into the blood vessel that feeds the organ.

“In a pig model, giving that equivalent dose of cells actually caused the area of damage in the heart to shrink,” said Smith.

New paper furthers cell reprogramming

The new research follows several recent cell reprogramming discoveries involving cells in other organs, said Dr. Arnold Kriegstein, director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF.

Earlier this year, a team at Stanford University reported that they had reprogrammed an adult skin cell to become a neuron-like cell. And in 2008, scientists reprogrammed one type of cells found in the gut – exocrine cells – into another type, endocrine cells.

“This paper follows on the heels of those two discoveries,” said Kriegstein, “and it provides fascinating potential applications.”

This beating heart cell video was produced by the Gladstone Institutes' researchers.

More video:
Watch QUEST TV's segment about stem cell research, called Stem Cell Gold Rush.

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This story marks the first time I've had to use a pseudynm to protect the identity of a horse.

"Disney's" owner's desire for privacy only underscores the stakes here. Performance horses at his level can be worth $60,000 and more. Training, too, is an enormous investment. "Gretchen," as we call her in the piece, has spent years training Disney in English dressage (which, incidentally, makes for some very entertaining YouTube viewing if you have some time to kill). And so when she noticed that her horse's gait had started to suffer, she jumped to find a treatment.

Speed is key here, it was explained to me, because the smaller the injury, the better a horse's chance for recovery. Emphasizing that point is one of the main reasons Gretchen agreed to take part in this program. She says too many owners treat their horses' injuries with ever-greater doses of painkillers, delaying real treatment until it's too late. Gretchen estimated that, including all the preliminary visits and tests, Disney's treatment may reach $7,000.

Davis vets couldn't provide statistics on whether this treatment – injecting a horse's mesenchymal stem cells, drawn from the marrow of the animal's sternum, into the same animal's torn tendon – succeeds in producing new tendon tissue. (Part of the problem is that it's hard to distinguish tendon tissue from scar tissue, seen through an ultrasound.) But if it works, they believe humans may one day have another option for treating our torn ligaments, too.

Listen to the Stem Cells and Horses radio report online, and watch our Web Extra Slideshow.

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Soon after Barack Obama is sworn in as President next week, he is expected to reverse George Bush’s executive order limiting embryonic stem cell research. Scientists say their research has been stifled by restricting them to existing stem cell lines. The resulting boom in this cutting-edge medical technology will benefit California's research institutes in a big way.

Researchers call stem cell technology a "revolution" in medicine, along the lines of the development of antibiotics in the 1940s, or the manufacturing of insulin and other therapies from recombinant DNA breakthroughs.

But why do stem cells offer such promise?

Robert Klein, chair of the governing board for the California Institute of Regenerative Medicine (the state stem-cell agency created by Proposition 71), says that the recombinant DNA revolution in the 1970s saved the life of his son, and that the potential for saving lives is even greater with stem cell work.

Stem cell technology has only existed for a decade. And despite the Presidential ban on use of new lines of embryonic stem cells, the advances in research have happened quickly. And, according to Deepak Srivastava, Director of Cardiovascular Research at the UCSF Gladstone Institute, the many possible applications of stem cell work will be seen in the short term (over the next few years) and long term (regeneration of damaged organs could happen in 7 to 10 years, he says).

Dr. Srivastava says, in the case of one of his patients, five-month-old Ryder Ortiz, stem cell technology could have been a godsend. And it might still BE a godsend, he adds. Ryder was born without a left ventricle, the heart chamber that shoots blood into the body. With stem cell technology, it may become possible to grow a new ventricle, and that would’ve been a huge boon to the infant Ryder.

But here's the thing: Doctors jerry-rigged Ryder's circulatory system, and it's a process that works – until the patient hits his teen years. In many cases, that’s when the re-worked circulatory system fails. Now, if Dr. Srivastava's estimate is correct, and the technology develops in the next 7 to 10 years, that will be just in time for Ryder Ortiz, who will be inching nearer to adolescence at that time.

Listen to the New Life for Embryonic Stem Cell Research radio report online.

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ABC, Yahoo! and others ran a story about a woman who had a liver transplant whose blood type ended up changing. I love stories like this.

Not because of the change itself. Most likely, stem cells traveled from the new liver to the patient’s bone marrow. There, the stem cells set up shop and gave her a new blood type.

What intrigues me is what these types of stories mean for solving crimes. Because changed blood type usually means changed blood DNA. In other words, her blood cells now have different DNA from the other cells in her body. This can really confound an investigation if the police aren’t careful.

Of course this was a very rare event. But bone marrow transplants aren’t. And every bone marrow transplant results in blood cells with different DNA compared to the rest of the recipient’s cells.

Imagine that someone who has had a bone marrow transplant does something wrong and leaves blood behind at the crime scene. The police do a cheek swab to gather DNA evidence and check it against the police DNA database as well as likely suspects (including our bone marrow recipient).

The police don’t catch our bone marrow recipient because his cheek DNA is different than his new blood DNA. So he is off the hook (as long as the police don’t check the blood too). But they do get a match and arrest someone—the donor.

Sounds weird but something almost like this complicated a case in Alaska a few years ago. There was a serious crime and a semen sample from the crime scene matched a known criminal’s DNA. But the person whose DNA matched the DNA from the crime scene had a strong alibi…he was in jail at the time! So what happened?

A little further investigation showed that the guy in jail had received a bone marrow transplant from his brother. And his brother was the one who committed the crime.

This one worked out all right in the end. But what would have happened to the brother if he weren’t in jail at the time? Would an overworked public defender have figured something like this out? The guy was lucky he was already in jail!

So people with bone marrow transplants need to be careful. And the police need to be careful about what sample they take from suspects.

Dr. Barry Starr is a Geneticist-in-Residence at The Tech Museum of Innovation in San Jose, CA.

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