Now, scientists in San Francisco say a more effective treatment might be on the way.

Three months after being injected with three genes, the hearts of mice that had suffered a heart attack pumped as much blood as a normal heart. Credit: Gabriela Quirós, QUEST

The researchers from the Gladstone Institutes, affiliated with the University of California-San Francisco, reported today that using a new genetic technique, they have succeeded for the first time in repairing, from within, the hearts of mice weakened by heart attacks.

“There are a variety of approaches we use right now to help people who are left with damaged hearts,” said Dr. Deepak Srivastava, senior author of the paper and director of cardiovascular research at the Gladstone Institutes, “but none of them actually get to the root of the problem, which is replacing that damaged heart muscle. And that’s where our focus has been.”

The scientists injected three genes into the hearts of research mice that had been given mild heart attacks. Within three months, the genes transformed non-beating cells in the heart into cells that looked and acted just like beating heart muscle cells. These new beating cells restored the heart’s ability to pump blood to the rest of the body.

Human hearts have billions of non-beating cells, which support the beating cells by forming the heart’s structure, Srivastava said. Mice have millions of these support cells too. When a heart attack happens, the support cells rush to the site of the damage and form scar tissue, which preserves the heart’s structure, but doesn’t help it pump blood.

“We’ve found a way to take these support cells that should normally never become muscle, and convert them into new muscle cells that actually integrate with the rest of the heart, contribute to the force that it generates, and allow us to regenerate the heart from within the organ itself,” said Srivastava.

Non-beating heart cells became beating heart cells like these. Credit: Li Qian, Gladstone Institutes

The new research appears in the April 18 online edition of the journal Nature and was led by Li Qian, also from the Gladstone Institutes.

Heart attacks and other heart disease kill 600,000 people each year. Many more survive, yet lead diminished lives. Some 5.7 million people live with damaged hearts that pump less blood, making it difficult for them to climb a flight of stairs or walk across a parking lot.

During a heart attack, clots block one or several coronary arteries and cut off blood flow. By rushing patients to the operating table and unclogging their arteries with catheters and stents, doctors are able to save all but 5 percent of victims who make it to the hospital.

“While we’ve been doing better at saving lives, each time we save a life the patient still loses some of their muscle,” Srivastava said. “So the number of people who are left with damaged hearts is actually growing, even though the number of people who die from heart attacks is getting smaller.”

Treatments for humans could be six to seven years away, he added. The next step will be to test the treatment on pigs. Scientists still need to figure out if cell reprogramming is safe for humans; how to deliver the genes into the heart, and how to produce enough new beating heart cells to repair a human – rather than a mouse – heart.

Nevertheless, the research is drawing the attention of other heart researchers.

“It’s a major discovery and certainly suggests a new approach to treat injury that previously had been thought to be irreversible,” said Dr. Eduardo Marbán, director of the Cedars-Sinai Heart Institute in Los Angeles.

Marbán said it’s been “a long-held dogma” that once scar tissue has formed in the heart, it can’t change into heart muscle. This finding in mice, and recent research by Marbán’s team on a small group of human patients, challenge that belief, he said.

Although the cell reprogramming research doesn’t involve stem cells, the Gladstone scientists used techniques that were discovered through stem cell research.

The scientists said their work was inspired by the discovery in 2007 that a few genes can transform an adult skin cell into a cell with the properties of a human embryonic stem cell. Researchers have been intensely interested in embryonic stem cells as a possible source of treatments for diseases like Parkinson’s because they can be coaxed to turn into virtually any type of cell in the body. But because embryonic stem cells are plucked from embryos left over from fertility treatments, and require the destruction of these embryos, their study has been controversial.

An alternative to embryonic stem cells came with the skin cell breakthrough five years ago. Then, Dr. Shinya Yamanaka, of the Gladstone Institutes and Kyoto University in Japan, inserted four genes that are present in embryonic stem cells into adult skin cells. The four genes reprogrammed the skin cells to become embryonic-like stem cells.

That led scientists to look for a way to transform one type of adult cell into another type of adult cell without the need to create stem cells at all.

“Yamanaka opened up the idea that adult cells weren’t permanently fixed,” said Srivastava. “That led us to ask whether or not we could convert one of these heart support cells into a heart muscle cell.”

Bypassing the creation of stem cells has several advantages. Though stem cells are versatile, when they’re introduced into the body they can behave as cancer cells and form tumors.

“It’s a dramatic and heady possibility that vindicates for the first time the idea that we might be able to harness truly regenerative medicine,” Marbán said.

Embryonic stem cells like these won't be helping patients by 2014 but they will probably help them one day in the future. Image courtesy of PLOS Biology.

Remember back in 2004 that big debate about whether California voters should fund embryonic stem (ES) cell research? It passed and now 8 years later, people are starting to ask what we have to show for it. It's more than you might think…

First off, though, there are no cures using ES cells in the offing. The money spent so far has gone into recruiting, setting up labs, basic research, and so on. This has laid the foundation from where eventual cures can come.

In fact, before going any further, it is important to reflect a bit on what was happening in 2004. President Bush had restricted ES cell research to the point where very little meaningful research could go on here in the U.S. And researchers were starting to vote with their feet.

Key stem cell researchers in the U.S. began to talk about going to places like England and Singapore where they could do their research. There was a real worry the U.S. would be left behind and that this would keep U.S. researchers away from the forefront of biological research for the first time in our history. It was a frustrating, scary time for scientists.

Of course it was an awful time for people suffering from awful incurable diseases too. They were worried that cures involving ES cells would not come in time for them unless research was done in a big way here in the U.S.

In swooped Proposition 71 to save the day. It provided 3 billion dollars of funding for ES cell research here in California. At a minimum it provided stopgap funding to keep ES cell research alive and well here in the U.S. until President Obama re-opened the spigots again in 2009.

Even if this is all Proposition 71 accomplished, I would argue it was worth it. Eventual cures using these cells are 5-6 years closer than they would be without the money spent by California voters. This is a big deal to patients suffering from all those life threatening diseases we always hear about.

Unfortunately this probably isn’t what Californians voted for. If media reports from then and now are to be believed, they expected cures not basic research. They wanted the paralyzed to walk, Alzheimer’s patients to remember and Michael J. Fox to return to being Alex P. Keaton or Marty McFly.

These were unrealistic expectations then and they still are today. There was no way something as new and complex as ES cells was going to generate a cure in just a few years or even a decade. (Of course one thing is certain, without research ES cells would never cure anything.)

I can remember back in 2004 thinking proponents were overselling this proposition. I spoke with a lot of scientists at the time and they all agreed. But what I don’t remember and am having trouble reconstructing is who did the overselling.

Ads like this one don’t seem to overpromise, they just talk about what we might be able to get out of ES cell research:

Whatever the reason for these inflated expectations, scientists everywhere are going to have to deal with the fallout of a disappointed voting public. They are going to either have to come up with cures fast (unlikely at least with ES cells) or explain why expectations have not been met. And this isn’t just a concern for stem cell researchers.

This has the potential to impact lots of science research as unfulfilled promises causes an increasingly skeptical public to become more so. Scientists will need to show that they did not overhype this or explain why they oversold it in the first place. Neither sounds too enticing.

More Information:

California's stem cell agency ponders its future

California stem cell research: Were voters duped?

California Institute for Regenerative Medicine (CIRM)

Geron both pulls out of the first clinical trial of embryonic stem cells and the entire research area

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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