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.

By one estimate, there are 10 million alcoholics in the US. Photo Credit: Ralf Roletschek

Joseph McHugh is an artist who lives in San Francisco. Like his father before him, Joe had always been a drinker. But recently, it started to pick up.

“It sort of got out of control,” he says. “It wasn’t starting at five o’clock, it was starting at noon, when I’d have a couple shots and so forth.”

He was having blackouts, he says. He remembered nothing, but people would tell him stories of what he’d done. “Like what?” I ask him.

“Things I don’t want to even mention, ok?”

What brought McHugh VA Medical Center in San Francisco was a heart attack. It literally terrified him into sobriety. He's been dry a month now, slogging through recovery with other men whose lives have also become simply untenable.

Listen to the QUEST radio story The Search for Alcoholism's Miracle Drug

McHugh’s story is a familiar one to doctors who treat alcoholism, like Peter Banys, Director of Substance Abuse Programs at the VA.

“It's always a crisis,” Banys says. “And it can be a marital crisis, a family crisis, or job termination.”

Alcoholism is a very treatable disease, says Banys. Because of all the recent research, people like McHugh have more options than ever, including AA, therapy, and medication, which can be effective in preventing relapse.

Still, there are some challenges. First of all, the meds are a tough sell, Banys says. He says his patients often think of their alcoholism as a moral weakness.

“One of the things we hear a lot,” he says, “is I don’t want to depend on a drug. They’ve been depending on a drug for 25 years, they don’t want to depend on ours.”

Another problem is that drugs that once seemed promising have often fallen short.

Take Naltrexone, which was approved in 1995. Naltrexone blocks the brain’s opioid receptors, which make alcohol feel good.

“That was the great hope,” says Banys. “It kind of crumbled in our hands.”

On many people, Natrexone has no effect all. They’re just wired differently.

And that’s proven to be a useful insight.

“One of the things that we have to make clear is that alcoholism is almost certainly not a single disease or disorder. I believe that in the near future, we will be talking about “the alcoholisms.”

The fact of these “alcoholisms” means that researchers are now targeting specific kinds aspects of brain chemistry that might be involved in alcoholism.

Howard Fields directs Human Clinical Research at the Gallo Center in Emeryville, an institute devoted to alcoholism and addiction, affiliated with The University of California, San Francisco.

What interests him is something familiar to many of us: Impulsivity. Different people are impulsive to different degrees, just like rats, and other animals. From an evolutionary standpoint, this makes sense.

“You want someone who would throw themselves on the hand grenade and save the lives of other people,” says Fields. “The same people who wind up in prison might be completely different in a battlefield situation. They might be the heroes.”

But in regular life, impulsivity can be a dangerous trait to have, says Fields. “If you score high for impulsivity, you are at greater risk to actually become an abuser or an addict. There’s no question about that.”

Fields says that in some people, impulsivity can be traced back to a specific gene. If you have it, you’re more likely to be impulsive. And it turns out, there is already a drug on the market that targets a function of this gene. It’s called tolcapone, and it’s prescribed to people with Parkinson’s disease.

So what Fields aims to find out is whether tolcapone might actually make people less impulsive. And if that’s true, whether it can help people limit their drinking. This research is now in human clinical trials.

Of course, even if the drug works for some people, it won’t work for everyone. The fact that there are “alcoholisms,” as Peter Banys put it, means that there may never be a single miracle drug.

But whatever the future holds, the goal of treatment will always look more or less the same: More people like Joseph McHugh, who have made the life-changing decision to get and stay sober.

McHugh says it’s hard to know what things will be like, once he’s out of rehab and back with his family. But he’s optimistic.

“I’m sort of glad that everything is where it is now. Because it is a change. It’s a necessary change."

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The nose of the star-nosed mole is much more sensitive than the human hand. Credit: Dr. Ken Catania, Vanderbilt University

Pain is the most common reason for trips to the doctor's office. So it makes sense that pain treatment is a huge part of our healthcare system, costing more than 100 billion dollars a year. But how exactly pain works is still a mystery in many ways.

Like any normal 9-year-old, Maddie Burkhardt was playing outside with her friends last summer, racing around in a pedal go-cart.

"And my foot slipped and it went under the go-cart. Like it got bent backwards," she says.

Maddie broke a bone in her foot. So, her mom, Danielle, took her to see a podiatrist, who put her in a series of casts.

"And every time he took the cast off, he said 'ok, you should feel much better now.' And she was just like 'no, it's killing me," says Danielle.

As the weeks went by, it became clear that Maddie's pain wasn't normal. "She would not allow anything to touch her foot at all. And we didn't really know what was going on," says Danielle.

Listen to the QUEST radio story The Science of Pain

Even a light touch, like the wind blowing, was incredibly painful. "It felt like there was knives in my foot. Like a big elephant smashing on your foot or something," says Maddie.

Maddie was diagnosed with complex regional pain syndrome and ended up in a special treatment program at Lucile Packard Children's Hospital in Palo Alto.

Dr. Elliot Krane, who heads the program, says "most of the time, pain is the signal that there's a problem and it's a useful sensation to have and a protective one."

But sometimes, our body's warning system goes haywire, like in Maddie's case. Nerve cells send out pain signals even when there's no reason to.

"It's a terrible pain problem," says Dr. Krane. "And it's one that we really don't understand the origins of. And because we understand so little about it, our therapy of it is also very rudimentary.

Krane says Maddie, like most patients, went through a slew of treatments, like physical therapy and pain medication. It took months to recover. "I can't exactly run really yet, but I can walk faster and I can play with my friends and do a lot more," Maddie says.

For the most part, doctors rely on opiates like morphine to control pain. But those drugs aren't very targeted. The challenge is that pain is very difficult to study. "There's other things and other processes in the body which are measurable in some objective fashion: heart rate, blood pressure, temperature. But how do you measure pain?" asks Dr. Krane.

Looking to Nature for Solutions

In a lab at the University of California-Berkeley, Diana Bautista has the same questions about pain. "Many people are trying to figure out how to do this. And we decided to look to nature to solve this problem."

Bautista is an assistant professor of biology at the University of California-Berkeley. She's peering into a large plastic tub filled with dirt.

A star-nosed mole at UC Berkeley. Photo: Kristin Gerhold, Bautista Lab.

"So, if you look here in the corner of the dirt, you can see that there's a star-nosed mole. Pretty interesting looking, right?"

Star-nosed moles have a very unique look. Their large pink nose has 22 finger-like tentacles that they use to feel for food in the dark tunnels where the live.

"What we don't see, that you need special high-speed video to see, is that they're actually tapping very rapidly the surface," says Bautista.

Compared to our fingertips, the mole's star has 10 times more nerve cells. "It's much more sensitive than the human hand."

That lack of sensitivity in human skin makes it difficult to study pain, because our nerve endings are so spread out.

We also have about 20 different kinds of nerve cells. Some detect pain, some detect light touch. Others detect hot and cold. "And so it's very difficult to study one in isolation or to separate the pain cells from the light touch cells."

That's where the star-nosed mole comes in. Its star is densely packed with light touch cells, but not a lot of pain cells. So Bautista says, studying tissue samples of the mole's star can reveal the differences between nerve cells.

"How does one cell feel the prick of the pin and the other feel the feather? We don't know what happens in those nerve endings," says Bautista.

Bautista says knowing what happens in normal nerves can tell a lot about when nerves don't work normally – like when diabetes patients experience numbness or cancer patients have hypersensitivity. That comes down to the biochemistry inside the cells. For that, Bautista is also studying another organism.

Peppers Targeting Nerve Cells

"These are Szechuan peppers that are from the Chinese prickly ash," Bautista says, handing me the peppercorns.

"Chew them a little bit in the front of your mouth."

As I chew, my tongue becomes slightly numb. "It feels like a little buzzing, tingling sensation," says Baustista.

The peppercorns aren't hot, but they do have chemicals that are working on my sense of touch. "We know that they target special receptors and cause those nerves to be excited just as if somebody was tickling your tongue," says Bautista.

That's a trick that humans could copy. "By indentifying the molecular mechanisms, we could really go in and design better drugs and come up with better therapies and alternatives for treating conditions like chronic pain," she says.

Bautista hopes the research will lead to more targeted pain drugs, so patients like Maddie Burkhardt will have an easier recovery.

Check out the star-nosed mole in action:

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It probably goes without saying — the dentist’s chair isn’t the most popular place to visit. But going to the dentist may one day be a very different experience. Researchers at the University of California San Francisco are developing new technology that may make a dentist’s drill less common.

Inside one of the treatment rooms at the UCSF School of Dentistry, Dr. Peter Rechmann is holding a small tool that could be a very big leap forward in dentistry — a laser. Unlike that familiar drill we love to hate, a laser drills into a tooth without making contact.

Listen to the QUEST radio story Visiting the Dentist Chair of the Future.

“So you don’t feel vibration. Yes, you hear the sound, you hear the tck tck tck, but that’s it,” says Rechmann. That makes a big difference, especially when Rechmann is working with younger patients. “Kids typically fear things more than adults. And they don’t care, they like it. Sometimes they say, ‘Oh, that was interesting’.”

Lasers have been used in dentistry for about a decade, but mostly on soft tissues like gums. Rechmann says laser drills are becoming more common now that the cost is coming down. And he expects lasers to soon play an even bigger role by actually helping to prevent cavities.

Rechmann holds a pulled tooth and fires short laser pulses at a small area on the outside. “The temperature on the enameled surface gets heated up to between 400 and 1000 degrees Celsius. It sounds terrible but it’s not. It’s really just the outer surface,” he says.

The extreme temperature slightly alters the make up of the outer tooth enamel which, Rechmann says, makes it more resistant to tooth decay. They’re now testing the treatment in clinical trials and it could be available in one to three years.

“If you treat this once, OK, you should still keep on brushing your teeth, but it’s really strongly protecting your teeth,” says Rechmann.

Of course, what our teeth really need protection from are our own bacteria. They’re specially adapted to live in our mouth, which, with all the food we chew, is a pretty nice place to call home.

“It’s a very nice place. It’s nice and warm and comfortable,” says John Featherstone, Dean of the UCSF School of Dentistry.

“Bacteria produce acid – that’s their major waste product. And that acid dissolves the enamel in the teeth.” Featherstone says in the past, dentistry has been focused on cleaning up the damage done by these bacteria. Now, he also sees the field moving towards prevention.

“If we can diagnose as we can now early on, what it tells us is that there’s disease process going on and we have to halt the disease process,” says Featherstone.

But given our teeth brushing habits – or lack thereof – Featherstone says there will probably always be a need to fill cavities. But what if cavities could fill themselves?

Self-Filling Cavities

Stefan Habelitz is standing in front of a refrigerator that holds 20,000 pulled teeth, collected from local dental clinics. Habelitz is a material scientist. He studies the structure of teeth.

“It’s amazing, a really amazing structure. For an engineer, it’s a real feast,” says Habelitz.

Tooth enamel is the hardest substance in our body. It’s designed to break apart foods like seeds or hard candy. “But if it can’t, it will release stress by forming fractures, by forming cracks,” Habelitz says.

Those tiny cracks are actually good — they’re part of the tooth’s design. They prevent it from being broken by one big crack. The problem with our teeth, Habelitz says, is that unlike our bones or skin, we can’t regrow tooth enamel. At least, not by ourselves.

“So let’s just drop these teeth in here.” Habelitz takes a few teeth with very large cavities and drops them into a beaker filled with a special solution. Tooth enamel is made of a mineral – so Habelitz says it’s not too difficult to remineralize or rebuild the enamel. That’s something the fluoride in toothpaste helps do.

“But once the bacteria makes it through the enamel, then it has been so far impossible to remineralize these legions,” says Habelitz.

That’s because deeper in the tooth in the material called dentin, minerals are mixed with organic structures, which are much harder to regrow. What Habelitz has in this beaker is a special compound that regrows the minerals and bonds them to the organic structures.

“So only when that link is established, the tissue that you build up again actually will be strong enough and stiff enough to support the pressure that you apply when you chew on your teeth,” he says.

One day, Habelitz says this process could be done right inside a patient’s mouth. The problem now is the process takes a long time — several weeks to fill a small cavity. “It should be an approach that needs to be done at least within a day, ideally within a few minutes.”

Habelitz is working to speed up the process, though it will be years before it’s available. But even if he and his colleagues can only regrow a small amount of a tooth, that’s part of a tooth that doesn’t have to be filled.

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Stanford University.

On Wednesday, scientists at Stanford Medical School released new images they’ve produced showing a slice of a mouse’s cerebral cortex. The images, captured using a technology called array tomography, show individual neurons and synapses. Synapses – which are less than a thousandth of a millimeter in diameter – allow brain cells to communicate with each other.

The idea, said Stephen Smith, a professor of molecular and cellular physiology at Stanford Medical School, is that one day scientists might be able to map the changes in individual synapses that occur when people, say, learn a new skill, or experience pain or disease.

That’s a tall order, considering the number of synapses there are in a human brain. Smith says in the human cerebral cortex alone, there are 125 trillion synapses – as many stars as you’d find in 1,500 Milky Ways.

These images – set, in this video, to music composed by Smith’s daughter – are a step in that direction. Smith said the images “have revealed to me, in a way I wasn’t entirely prepared for, how incredibly beautiful the insides of the brain are.”

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You've probably heard about some of the breakthroughs in personal genome sequencing, where companies take a look at your DNA and send back your risk profile. That can be confusing information to have (check out this post from Quest blogger Dr. Barry Starr for his take on it). But there's a flip side to all this genetic research that doesn't have to do with risk: personalized medicine. That's where doctors can customize medical treatments to fit your genetic profile.

Right now, there are only a handful of drugs that are labeled with genetic information, so doctors can take it into consideration. (Here's an article from the New York Times that gives an overview).  But that doesn't mean existing medications are left out.  I spent some time with Deanna Kroetz in this story, who studies pharmacogenomics at UC San Francisco.  She explained that differences in our DNA can cause some of us to process drugs at different rates. We all metabolize drugs with enzymes in the liver, but based on expression of our DNA, we may have different levels of enzymes or our enzymes may not function as well.

There are plenty of other things that affect how we process drugs, like our diet or other drugs we're taking. But these genetic differences mean some people metabolize drugs quickly and others metabolize them slowly. One example that many people are familiar with is codeine.  Codeine is converted into morphine by our bodies and it's the morphine that actually has an effect — but that conversion depends on a particular enzyme. Some people have very low levels of the enzyme that's needed, so codeine doesn't do much for them.

They're also studying another drug response mechanism at UCSF and it has to do with our cells. Many drugs have to go inside our cells in order to have an effect, but if you think back to high school biology, you might remember that cells are protected by membranes.  It takes transporters – those special gatekeepers sitting on the cell membranes — to allow things in.  They also can spit things out of cells.

I spent some time in the lab with Rachel LaFond, a graduate student at UCSF.  She was running experiments on one particular transporter known as ABCG2. This transporter is particularly good at spitting things out of cells. Normally its job is to kick toxins out, but some cancers have been able to hijack this machinery.  Cancer cells with an over expression of this transporter can spit out chemotherapy drugs, which means they aren't helping the patient.  LaFond is working to understand this variation better, so they could one day develop a genetic test for it.

Listen to the Personalized Medicine radio report online.

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Hi everybody. I want to let the QUEST community know that over at KQED’s Health Dialogues, we just launched a new project, called Healthy Ideas: Californians Weigh In on Health Care Reform.

In his 100th day press briefing a few days ago, President Obama reiterated his desire to enact health care reform by the end of 2009. The President has also put out a call to all Americans to submit our ideas on just how to do that. So, Health Dialogues decided that we’d let Washington know what Californians think.

Is the cost of new medical technologies worth the potential health benefits? What can we do to eliminate health disparities across socioeconomic backgrounds? Should everyone be required to purchase health insurance?

Healthy Ideas is a conversation among academics, health care professionals, policy think tanks and the general public about what kind of health care reform California wants and needs. During the next two months, you can join the dialogue by reading our authors’ weekly posts, rating them and contributing your own thoughts and questions. At the end of the project, on July 1, we’ll summarize your ideas and deliver them to California’s representatives in Washington, as well as the Obama Administration, Senate Finance Committee Chairman Max Baucus and Senate Committee on Health, Education, Labor and Pensions Chairman Edward Kennedy.

To contribute your thoughts and let Washington know what kind of health care reform you want, join the dialogue at Healthy Ideas: Californians Weigh In on Health Care Reform.

Thanks!
Nick Vidinsky
Producer, Health Dialogues

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Scientists gather samples on the ocean floor.
Credit: Roger Linington.

What's different about the work being done at the UC Santa Cruz Chemical Screening Center is that it a) looks to a largely unexplored medical resource: the ocean, and b) uses robots, rather than "forlorn-looking grad students" (to quote Center director Scott Lokey) to run the tests.

Here's a video I shot of one of those robots in action, with Lokey narrating.

One thing that didn't make it into the piece is that these researchers — including Lokey and Roger Linington — aren't just studying every disease they can think of. They focus on the diseases that commercial drug companies tend to neglect because there's so little profit in treating them – things like African sleeping sickness and cholera. So far, they're seeing progress on both, as well as breast cancer.

Listen to the Medicine from the Ocean Floor radio report online and check out images from this story in an online slideshow.

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