CIRM Scholar Jessica Gluck on using stem cells to make biological pacemakers for the heart

As part of our CIRM scholar series, we feature the research accomplishments of students and postdocs that have received CIRM funding.

Jessica Gluck, CIRM Scholar

Jessica Gluck, CIRM Scholar

I’d like to introduce you to one of our CIRM Scholars, Jessica Gluck. She’s currently a Postdoctoral Fellow at UC Davis working on human stem cell models of heart development. Jessica began her education in textiles and materials science at North Carolina State University, but that developed into a passion for biomedical engineering and stem cell research, which she pursued during her PhD at UC Los Angeles. During her graduate research, Jessica developed 3D bio-scaffolds that help human stem cells differentiate into functioning heart cells.

We asked Jessica to discuss her latest foray in the fields of stem cells and heart development.


Q: What are you currently working on in the lab?

JG: I work as a postdoc at UC Davis in the lab of Deborah Lieu. She’s working on developing pacemaking cardiomyocytes (heart cells) from human induced pluripotent stem cells (iPS cells). Pacemaking cells are the cells of the heart that are in charge of rhythm and synchronicity. Currently, we’re able to take iPS cells and get them to a cardiomyocyte state, but we want to further develop them into a pacemaking cell.

So ultimately, we’re trying to make a biological pacemaker. We can figure out how we can make a cell become the cell that tells your heart to beat, and there’s two things we can get out of that. First, if we understand how we get these beating cells, the ones that are telling the other heart cells to beat, we might be able to understand how different heart diseases progress, and we might be able to come up with a new way to prevent or treat that disease. Second, if we understand how we’re getting these pacemaking cells, we could hopefully bioengineer a biological pacemaker so you wouldn’t necessarily need an electronic pacemaker. With a biological one, a patient wouldn’t have to go back to the doctor to have their battery replaced. And they wouldn’t have to have multiple follow up surgeries throughout their life.

Q: What models are you using to study these pacemaking cells?

JG: I’m looking at my project from two different directions. On one side, we’re using a pig model, and we’re isolating cells from the sinoatrial (SA) node, which is where the pacemaking cells actually reside in your heart. And there’s really not that many of these cells. You probably have about a billion cells in your heart, but there’s maybe 100,000 of these pacemaking cells that are actually controlling the uniform beating of the heart. So we’re looking at the native SA node in the pig heart to see if it’s structurally any different than ventrical or atrial heart tissue.

Diagram of the heart depicting the Sinoatrial Node. (Image from Texas Heart Institute.

Diagram of the heart depicting the Sinoatrial Node. (Image from Texas Heart Institute)

We’ve found that the SA node is definitely different. So we’re de-cellularizing that tissue (removing the cells but not the matrix, or support structure, that keeps them in place) thinking that we could use the native matrix as a scaffold to help guide these heart cells to become the pacemaking phenotype. On the other side, we’re taking dishes with a known elasticity and we’re coating them with different proteins to see if we can tease out if there’s something that an individual protein does or a certain stiffness that actually is part of the driving force of making a pacemaking cell. We’ve gotten some pretty good preliminary results. So hopefully the next phase will be seeing how functional the cells are after they’ve been on these de-cellularized matrices.

Q: Why does your lab work with pig models?

JG: Pig hearts are pretty close to the human heart – their anatomy is pretty similar. To give you context, a pig heart is slightly larger than the size of your two hands clasped together. But the SA node, when you isolate it out, is only a couple of millimeters squared. It’s a lot smaller than we originally thought, and if we had gone with a smaller animal model, we wouldn’t be able to tangibly study or manipulate the SA node area. Because we are at UC Davis, we have a Meat Lab on campus, and we are able to get the pig hearts from them.

Q: Have you run into any road blocks with your research?

JG: For anybody that’s working with cardiomyocytes, the biggest problem is getting stem cells to become mature cardiomyocytes. Some labs have shown that you can get cells to a more mature cardiomyocyte after it’s been in culture for almost 100 days, but that’s not exactly feasible or that helpful.

We’ve been able to isolate out a small population of cells that we’re pretty sure are pacemaking cells. Over the last year, we’ve realized that a lot of the information that we thought we knew about pacemaking cells isn’t necessarily specific to pacemaking cells. Many of the biological markers that people have published in the literature are present in pacemaking cells, but we realized that they are also present in other heart cells like atrial cells, just in a lower amount. So we haven’t really been able to pick one specific biomarker that we’ve been able to say, yes this is actually a pacemaking cell. Instead, we have a small percentage of cells that we’re able to study. But we’re trying to figure out if there’s a way that we could increase our yield, or if there’s something fundamentally different about the environment that would also increase the yield of these pacemaking cells. So we’ve had a lot of trouble shooting along the way.

Q: What was your experience like as a CIRM scholar?

JG: I became a CIRM scholar in the spring of 2014. It was through the UC Davis Stem Cell Training Program. The opportunity was very helpful for me because it was in my first year as a postdoc at Davis. I earned my PhD at UCLA, so I was dealing with being on a new campus, trying to figure out whose lab I could go to to borrow random things and where to find equipment that I needed to use. So it was helpful to be around a group of other people that were also doing stem cell projects. Even though a lot of us were focused on different areas, it was still helpful to talk to other people, especially if you get somebody’s perspective that isn’t necessarily in your field. They might come up with a random idea that you haven’t thought of before.

Over the course of the year, we had a journal club, which was always interesting to see what’s going on in the field. I also went to the annual International Society for Stem Cell Research meeting in Vancouver using CIRM funding. And as part of the program, we also worked with the CIRM Bridges program between UC Davis and Cal State Sacramento. There were Bridges master’s students that were there with us. It was interesting to hear their take on everything, and they were very enthusiastic. We have had two master’s students work in our lab. I think it was very beneficial to them because they got a lot of hands on training and both have gone on to jobs in the regenerative medicine field.

Q: What is the future of stem cell research?

JG: If you’re looking at heart disease and stem cell treatments, there’s been some interesting clinical trials that have come out that have some promising results. I think that for a couple of those studies, people might have jumped the gun a little getting the treatments into the clinic. There’s still a lot that people should study in the lab before we move on to clinical trials. But I do think that we will see something in the next 20 years where stem cell research is going to have a huge therapeutic benefit. The field is just moving so quickly, and I think it will be really interesting to see what advances are made.

For our research, I’ve always been fairly realistic, and unfortunately, I don’t think we will see this biological pacemaker any time soon. But I think that the research that we produce along the way will be very beneficial to the field and our work will hopefully improve the foundation of what is known about pacemaking cells. What I think is really interesting about our lab’s work, is that we are moving into a 3D culture environment. Cells behave very differently in the body as opposed to on a plastic petri dish. So I think it’s very encouraging that we are seeing a lot more labs moving towards a more physiologically relevant model.

Q: What are your future goals?

I’ve been lucky that I’ve been able to work with very well established professors and also brand new faculty. But I’ve seen how difficult the funding climate is – it’s very daunting. So I’m really not sure what will happen next, and I’m keeping my options open.

I’ve really enjoyed working with our undergraduate and graduate students. I’ve gotten involved with outreach programs in Sacramento that promote science to young kids. It’s something that I’ve really enjoyed, and it’s very interesting telling people that I work in stem cells. Middle school kids seem to think that stem cells are magic. It’s fun to explain the very basics of stem cells and to see the light bulb moment where they understand it. I’m hoping to end up in a career that is still within the stem cell field but more towards teaching or outreach programs.

Q: What is your favorite thing about being a scientist?

JG: The thing I really like is having a puzzle that you’re trying to figure out the answer to. It’s great because every time you answer one question, that answer is going to lead you to at least three or four more new questions. I think that that’s really interesting especially trying to figure out how all the puzzle pieces fit together, and I’ve really enjoyed getting to work with people in very different fields. My parents think its funny because they said even as a little kid, I hated not knowing the answers to questions – and still do! They were completely understanding as to why I stayed in school as long as I did.

You can learn more about Jessica’s research by following her on Twitter: @JessicaGluckPhD

Regenerating damaged muscle after a heart attack

Cardio cells image

Images of clusters of heart muscle cells (in red and green) derived from human embryonic stem cells 40 days after transplantation. Courtesy UCLA

Every year more than 735,000 Americans have a heart attack. Many of those who survive often have lasting damage to their heart muscle and are at increased risk for future attacks and heart failure. Now CIRM-funded researchers at UCLA have identified a way that could help regenerate heart muscle after a heart attack, potentially not only saving lives but also increasing the quality of life.

The researchers used human embryonic stem cells to create a kind of cell, called a cardiac mesoderm cell, which has the ability to turn into cardiomyocytes, fibroblasts, smooth muscle, and endothelial cells. All these types of cells play an important role in helping repair a damaged heart.

As those embryonic cells were in the process of changing into cardiac mesoderms, the team was able to identify two key markers on the cell surface. The markers, called CD13 and ROR2 – which makes them sound like extras in the latest Star Wars movie – pinpointed the cells that were likely to be the most efficient at changing into the kind of cells needed to repair damaged heart tissue.

The researchers then transplanted those cells into an animal model and found that not only did many of the cells survive but they also produced the cells needed to regenerate heart muscle and vessels.

Big step forward

The research was published in the journal Stem Cell Reports. Dr. Reza Ardehali, the senior author of the CIRM-funded study, says this is a big step forward in the use of embryonic stem cells to help treat heart attacks:

“In a major heart attack, a person loses an estimated 1 billion heart cells, which results in permanent scar tissue in the heart muscle. Our findings seek to unlock some of the mysteries of heart regeneration in order to move the possibility of cardiovascular cell therapies forward. We have now found a way to identify the right type of stem cells that create heart cells that successfully engraft when transplanted and generate muscle tissue in the heart, which means we’re one step closer to developing cell-based therapies for people living with heart disease.”

More good news

But wait, as they say in cheesy TV infomercials, there’s more. Ardehali and his team not only found the markers to help them identify the right kinds of cell to use in regenerating damaged heart muscle, they also found a way to track the transplanted cells so they could make sure they were going where they wanted them to, and doing what they needed them to.

In a study published in Stem Cells Translational Medicine,  Ardehali and his team used special particles that can be tracked using MRI. They used those particles to label the cardiac mesoderm cells. Once transplanted into the animal model the team was able to follow the cells for up to 40 days.

Ardehali says knowing how to identify the best cells to repair a damaged heart, and then being able to track them over a long period, gives us valuable tools to use as we work to develop better, more effective treatments for people who have had a heart attack.

CIRM is already funding a Phase 2 clinical trial, run by a company called Capricor, using stem cells to treat heart attack patients.

 

Patching up a Broken Heart with FSTL1

Get-Over-Heartbreak-Step-08How do you mend a broken heart? It’s a subject that songwriters have pondered for generations, without success. But if you pose the same question to a heart doctor, they would give you a number of practical options that focus on the prevention or management of the physical symptoms you are dealing with.

That’s because heart disease is complicated. There are many different types of diseases that affect the health and function of the heart. And once damage happens to your heart, say from a heart attack, it’s really hard to fix.

New regenerative factor for heart disease

Scientists from Stanford University, the University of California, San Diego, and the Sanford-Burnham-Prebys Medical Discovery Institute have teamed up to figure out how to fix a broken heart. In a CIRM-funded study published today in the journal Nature, the group reported that the gene follistatin-like 1 (FSTl1) has the ability to regenerate heart tissue when it’s delivered within a patch to the injured heart.

2004_Heart_Wall

The different layers of the heart.

The wall of the heart is made up of three different layers: the endocardium (inner), myocardium (middle), and epicardium (outer). The epicardium not only protects the inner two layers of the heart, but also supports the growth of the fetal heart.

The group decided to study epicardial cells to determine whether these cells produced specific factors that protect or even regenerate adult heart tissue. They took epicardial cells from rodents and cultured them with heart cells (called cardiomyocytes), and found that the heart cells divided and reproduced much more quickly when cultured with the epicardial cells. This suggested that the epicardial cells might secrete factors that promote the expansion of the heart cells.

Patching up a broken heart

They next asked whether factors secreted from epicardial cells could improve heart function in mice after heart injury. They designed and engineered tiny patches that contained a cocktail of special epicardial factors and sewed them onto the heart tissue of mice that had just experienced the equivalent of a human heart attack. When they monitored these mice two weeks later, they saw an improvement in heart function in mice with the patch compared to mice without.

When they analyzed the cocktail of epicardial factors in the patch, they identified one factor that had potential for regenerating heart tissue. It was FSTL1. To test its regenerative abilities, they cultured rodent heart cells in a dish and treated them with FSTL1 protein. This treatment caused the heart cells to divide like crazy, thus proving that FSTL1 had regenerative qualities.

Moving from the dish into animal models, the scientists explored which layers of the heart FSTL1 was expressed in after heart injury. In healthy hearts, FSTL1 is expressed in the epicardium. However, in injured hearts, they found that FSTL1 expression was missing in the epicardium and was instead present in the middle layer of the heart, the myocardium.

FSTL1 to the rescue

patch

Cross sections of a healthy (control) or injured mouse heart. Injured hearts treated with patches containing FSTL1 show the most recovery of healthy heart tissue (red). Image adapted from Wei et al. 2015)

In a eureka moment, the scientists decided to add a FSTL1 protein back to the epicardial layer of the heart, post heart injury, using the same patch system they used earlier in mice, to see whether this would promote heart tissue regeneration. Their guess was correct. FSTL1 delivery through the engineered epicardium patch system resulted in a number of beneficial effects to the heart including better function and survival, reduced scar tissue build up (a consequence of heart injury), and increased blood flow to the area of the patch.

Upon further inspection, they found that the FSTL1 epicardial patch caused heart cells to divide and proliferate. The same effect did not happen when FSTL1 is expressed in the myocardium layer of the injured heart.

To make sure their findings translated to other animal models, they studied the regenerative effects of FSTL1 in a pig model of heart injury. They applied patches infused with FSTL1 to the injured heart and as expected, observed that FSTL1 delivery improved symptoms and caused heart cells to divide.

No more heartbreak?

The authors concluded that heart injury turns off the activity of an important factor, FSTL1, in specific heart cells needed for heart regeneration. By turning on FSTL1 back on in the epicardium after injury, heart cells will receive the signal to divide and regenerate heart tissue.

Co-first author and CIRM postdoctoral scholar Ke Wei spoke to CIRM about the next steps for this study and its relevance:

Ke Wei

Co-first author, Ke Wei

In the future, we hope that our engineered epicardium patch technology can be used as a clinical platform to deliver drugs or cells to the injured heart. This strategy differs from conventional tools to treat heart attack, and may provide a novel approach in our repertoire battling heart diseases.

Thus it seems that scientists have found a potential way to patch-up a broken heart and to extend a lifeline for those suffering from heart disease. It’s comforting to know that the regenerative abilities of FSTl1 will be explored in human models and will hopefully reach clinical trials.

Ke Wei (UCSD, Sanford-Burnham-Prebys) and Vahid Serpooshan (Stanford) were co-first authors on this study. The senior authors were Daniel Bernstein (Stanford), Mark Mercola (UCSD, Sanford-Burnham-Prebys), and Pilar Ruiz-Lozano (Stanford). Both Ke Wei and Mark Mercola received CIRM funding for this study.


Related Links:

10 Years/10 Therapies: 10 Years after its Founding CIRM will have 10 Therapies Approved for Clinical Trials

In 2004, when 59 percent of California voters approved the creation of CIRM, our state embarked on an unprecedented experiment: providing concentrated funding to a new, promising area of research. The goal: accelerate the process of getting therapies to patients, especially those with unmet medical needs.

Having 10 potential treatments expected to be approved for clinical trials by the end of this year is no small feat. Indeed, it is viewed by many in the industry as a clear acceleration of the normal pace of discovery. Here are our first 10 treatments to be approved for testing in patients.

HIV/AIDS. The company Calimmune is genetically modifying patients’ own blood-forming stem cells so that they can produce immune cells—the ones normally destroyed by the virus—that cannot be infected by the virus. It is hoped this will allow the patients to clear their systems of the virus, effectively curing the disease.

Spinal cord injury patient advocate Katie Sharify is optimistic about the latest clinical trial led by Asterias Biotherapeutics.

Spinal cord injury patient advocate Katie Sharify is optimistic about the clinical trial led by Asterias Biotherapeutics.

Spinal Cord Injury. The company Asterias Biotherapeutics uses cells derived from embryonic stem cells to heal the spinal cord at the site of injury. They mature the stem cells into cells called oligodendrocyte precursor cells that are injected at the site of injury where it is hoped they can repair the insulating layer, called myelin, that normally protects the nerves in the spinal cord.

Heart Disease. The company Capricor is using donor cells derived from heart stem cells to treat patients developing heart failure after a heart attack. In early studies the cells appear to reduce scar tissue, promote blood vessel growth and improve heart function.

Solid Tumors. A team at the University of California, Los Angeles, has developed a drug that seeks out and destroys cancer stem cells, which are considered by many to be the reason cancers resist treatment and recur. It is believed that eliminating the cancer stem cells may lead to long-term cures.

Leukemia. A team at the University of California, San Diego, is using a protein called an antibody to target cancer stem cells. The antibody senses and attaches to a protein on the surface of cancer stem cells. That disables the protein, which slows the growth of the leukemia and makes it more vulnerable to other anti-cancer drugs.

Sickle Cell Anemia. A team at the University of California, Los Angeles, is genetically modifying a patient’s own blood stem cells so they will produce a correct version of hemoglobin, the oxygen carrying protein that is mutated in these patients, which causes an abnormal sickle-like shape to the red blood cells. These misshapen cells lead to dangerous blood clots and debilitating pain The genetically modified stem cells will be given back to the patient to create a new sickle cell-free blood supply.

Solid Tumors. A team at Stanford University is using a molecule known as an antibody to target cancer stem cells. This antibody can recognize a protein the cancer stem cells carry on their cell surface. The cancer cells use that protein to evade the component of our immune system that routinely destroys tumors. By disabling this protein the team hopes to empower the body’s own immune system to attack and destroy the cancer stem cells.

Diabetes. The company Viacyte is growing cells in a permeable pouch that when implanted under the skin can sense blood sugar and produce the levels of insulin needed to eliminate the symptoms of diabetes. They start with embryonic stem cells, mature them part way to becoming pancreas tissues and insert them into the permeable pouch. When transplanted in the patient, the cells fully develop into the cells needed for proper metabolism of sugar and restore it to a healthy level.

HIV/AIDS. A team at The City of Hope is genetically modifying patients’ own blood-forming stem cells so that they can produce immune cells—the ones normally destroyed by the virus—that cannot be infected by the virus. It is hoped this will allow the patients to clear their systems of the virus, effectively curing the disease

Blindness. A team at the University of Southern California is using cells derived from embryonic stem cell and a scaffold to replace cells damaged in Age-related Macular Degeneration (AMD), the leading cause of blindness in the elderly. The therapy starts with embryonic stem cells that have been matured into a type of cell lost in AMD and places them on a single layer synthetic scaffold. This sheet of cells is inserted surgically into the back of the eye to replace the damaged cells that are needed to maintain healthy photoreceptors in the retina.

Cells’ Knack for Hoarding Proteins Inadvertently Kickstarts the Aging Process

Even cells need to take out the trash in order to maintain a healthy clean environment. And scientists are now uncovering the harmful effects when cells instead begin to hoard their garbage.

Cells' penchant for hoarding proteins may spur the cellular aging process, according to new research.

Cells’ penchant for hoarding proteins may spur the cellular aging process, according to new research. [Labyrinth (1986)]

Aging, on the cellular level is—at its core—the increasing inability for cells to repair themselves over time. As cells begin to break down faster than they can be repaired, the risk of age-related diseases escalates. Cancer, heart disease and neurological conditions such as Alzheimer’s disease are some of aging’s most deadly effects.

As a result, scientists have long searched for ways to give our cells a little help and improve our quality of life as we age. For example, recent research has pointed to a connection between fasting (restricting calories) and a longer lifespan, though the molecular mechanisms behind this connection remain somewhat cryptic.

But now Dr. Daniel Gottschling, a scientist at the Fred Hutchinson Cancer Research Center and an aging expert, has made extraordinary progress toward solving some of the mysteries of aging.

In two studies published this month in the Proceedings of the National Academy of Sciences and eLife, Gottschling and colleagues discover that a particular long-lasting protein builds up over time in certain cell types, causing the buildup of a protein hoard that damages the cell beyond repair.

Clearing out the Cobwebs

Some cells, such as those that make up the skin or that reside in the gut, are continually replenished by a stockpile of adult stem cells. But other cells, such as those found in the eye and brain, last for years, decades and—in some cases—our entire lifetimes.

Within and surrounding these long-lived cells are similarly long-lived proteins which help the cell perform essential functions. For example, the lens of the human eye, which helps focus light, is made up of these proteins that arise during embryonic development and last for a lifetime.

Dr. Daniel Gottschling is looking to unlock the mysteries behind cellular aging.

Dr. Daniel Gottschling is looking to unlock the mysteries behind cellular aging. [Image courtesy of the Fred Hutchinson Cancer Research Center]

“Shortly after you’re born, that’s it, you get no more of that protein and it lives with you the rest of your life,” explained Gottschling.

As a result, if those proteins degrade and die, new ones don’t replace them—the result is the age-related disease called cataracts.

But scientists weren’t exactly sure of the relationship between these dying proteins and the onset of conditions such as cataracts, and other disease related to aging. Did these conditions occur because the proteins were dying? Or rather because the proteins were building up to toxic levels?

So Gottschling and his team set up a series of experiments to find out.

Stashing Trash

They developed a laboratory model by using yeast cells. Interestingly, yeast cells share several key properties with human stem cells, and are often the focus of early-stage research into basic, fundamental concepts of biology.

Like stem cells, yeast cells grow and divide asymmetrically. In other words, a ‘mother’ cell will produce many ‘daughter’ cells, but will itself remain intact. In general, yeast mother cells produce up to 35 daughter cells before dying—which usually takes just a few days.

 Yeast “mother” cells budding and giving birth to newborn “daughter” cells.  [Image courtesy of Dr. Kiersten Henderson / Gottschling Lab]

Yeast “mother” cells budding and giving birth to newborn “daughter” cells.
[Image courtesy of Dr. Kiersten Henderson / Gottschling Lab]

Here, the research team used a special labeling technique that marked individual proteins that exist within and surrounding these mother cells. These microscopic tracking devices then told researchers how these proteins behaved over the entire lifespan of the mother cell as it aged.

The team found a total of 135 long-lived proteins within the mother cell. But what really surprised them was what they found upon closer examination: all but 21 of these 135 proteins appeared to have no function. They appeared to be trash.

“No one’s ever seen proteins like this before [in aging],” said Nathanial Thayer, a graduate student in the Gottschling Lab and lead author of one of the studies.

Added Gottschling, “With the number of different fragments [in the mother cell], we think they’re going to cause trouble. As the daughter yeast cells grow and split off, somehow mom retains all these protein bits.”

This startling discovery opened up an entirely new set of questions, explained Gottschling.

“It’s not clear whether the mother’s trash keeper function is a selfless act designed to give her daughters the best start possible, or if she’s hanging on to them for another reason.”

Hungry, Hoarding Mother Cells

So Gottschling and his team took a closer look at one of these proteins, known as Pma1.

Recent work by the Gottschling Lab found that cells lose their acidity over time, which itself leads to the deterioration of the cells’ primary energy source. The team hypothesized that Pma1 was somehow intricately tied to corresponding levels of pH (high pH levels indicate an acidic environment, while lower pH levels signify a more basic environment).

In the second study published in eLife, led by Postdoctoral Fellow Dr. Kiersten Henderson, the team made several intriguing discoveries about the role of Pma1.

First, they uncovered a key difference between mother and daughter cells: daughter cells are born with no Pma1. As a result, they are far more acidic than their mothers. But when they ramped up Pma1 in the mother cells, the acidity levels in subsequent generations of daughter cells changed accordingly.

“When we boosted levels of the protein, daughter cells were born with Pma1 and became more basic (they had a lower pH), just like their mothers.”

Further examination uncovered the true relationship between Pma1 and these cells. At its most fundamental, Pma1 helps the mother cells eat.

“Pma1 plays a key role in cellular feeding,” said Gottschling. “The protein sits on the surface of cells and helps them take in nutrients from their environment.”

Pma1 gives the mother cell the ability to gorge herself. The more access to food she has, the easier it is for her to produce more daughter cells. By hoarding Pma1, the mother cell can churn out more offspring. Unfortunately, she is also signing her own death certificate—she’s creating a more basic environment that, in the end, proves toxic and contributes to her death.

The hoarding, it turns out, may not all be due to the mother cells’ failure to ‘take out the trash.’ Instead, she wants to keep eating and producing daughters—and hoarding Pma1 allows her to do just that.

“There’s this whole trade off of being able to divide quickly and the negative side is that the individual, the mother, does not get to live as long.”

Together, the results from these two studies provide a huge boost for researchers like Gottschling who are trying to unravel the molecular mysteries of aging. But the process is incredibly intricate, and there will likely be no one simple solution to improving quality of life as we get older.

“The whole issue of aging is so complex that we’re still laying the groundwork of possibilities of how things can go awry,” said Gottschling. “And so we’re still learning what is going on. We’re defining the aging process.”

Finding your Inner Rhythm: Cedars-Sinai Cardiologists Create Biological “Pacemakers” in the Heart

If your heart has trouble keeping a steady rhythm, you normally get a pacemaker: a small device that is inserted into your body and attached to your heart. About 300,000 people receive a pacemaker each year. But what if we could harness the body’s own cells to do what an external device does today?

Cedars-Sinai cardiologists have discovered a new way to keep the heart beating in rhythm.

Cedars-Sinai cardiologists have discovered a new way to keep the heart beating in rhythm.

In research published today in Science Translational Medicine, cardiologists from the Cedars-Sinai Heart Institute have found a way to reprogram one type of heart cell into another type that actually keeps the heart beating at a steady rate. These findings, performed in animal models, open the door to replacing an artificial pacemaker with a natural, biological one.

Dr. Eduardo Marbán, CIRM-grantee and the study’s lead author, explained the importance of their research:

“We have been able, for the first time, to create a biological pacemaker using minimally invasive methods—and to show that the biological pacemaker supports the demands of daily life. We also are the first to reprogram a heart cell in a living animal in order to effectively cure a disease.”

In this study, researchers injected a gene called TBX18 into the hearts of laboratory pigs. They then monitored any changes in heart rhythms of those pigs, comparing them to the hearts of pigs that did not receive the injection.

In just two days, the pigs that had received the injection showed stronger, faster rhythms, compared to the controls. And even more importantly—that strong rhythm persisted for the entire duration of the study (14 days), indicating that the therapy could be sustainable as a longer-term alternative to traditional, artificial pacemakers.

Intriguingly, the research team argues that their new method could be especially useful in cases where a traditional pacemaker is not an option, such as in newborns. Dr. Eugenio Cingolani, another member of the Cedars-Sinai team explained:

“Babies still in the womb cannot have a pacemaker, but we hope to work with fetal medicine specialists to create a life-saving catheter-based treatment for infants diagnosed with congenital heart block. It is possible that one day, we might be able to save lives by replacing hardware with an injection of genes.”

In addition to newborns, this new method could help a variety of other heart disease patients unable to receive traditional pacemakers—such as those who would suffer certain negative effects, or more complex heart arrhythmias—should the research proceed to clinical trials, which they hope to begin in approximately three years.

Added Marbán:

“Originally, we thought that biological pacemaker cells could be a temporary bridge therapy for patients who had an infection in the implanted pacemaker area. These results show us that with more research, we might be able to develop a long-lasting biological treatment for patients.”

BIO International Panel Showed Stem Cell Science Poised to Make a Difference in Medical Practice Soon

When the biotechnology trade association began holding annual conferences in 1993, they drew 1,400 to the first event. This year BIO International expected nearly 20,000 here in San Diego. Among the dozens of concurrent sessions each day of this four-day scramble, stem cells got one track on one day this year. But listening to the progress being made by our presenters yesterday, our field is set to grow at the pace this meeting has—and could dominate the medical sessions here within the next decade.

995548_10151801308142804_405229409_n

After setting the scene with our opening panel yesterday, four subsequent panels confirmed the vast near-term potential painted by the opening speakers. They revealed a field maturing rapidly and starting to be a valued research tool of the bigger companies that have dominated the biotech industry, at the same time it is starting to deliver therapies to patients.

The second panel displayed the robust power of stem cells to model disease better than animal models ever could. These cells also let researchers dive much deeper into the genetic causes of disease, particularly diseases with multiple genes involved. Anne Bang from the Sanford-Burnham Institute mentioned her role in a consortium organized by the National Institutes of Health that is looking at the many genes involved in a type of heart weakening called left ventricular hypertrophy. Because different ethnicities tend to respond differently to drugs used for the condition, the consortium teams are creating iPS-type stem cell lines from 125 Caucasian patients and 125 African-American patients with various forms of the condition.

Their goal is to personalize and improve therapy across both patients groups. The way cells behave in the lab can tell the researchers much more relevant information than most animal models, so drugs developed based off their discoveries should have a better chance of success. All four panelists agreed that the field needs enough drugs developed with these tools to show that they do indeed have a better success rate. That track record should start to develop over the next few years.

The third panel talked about the shift in the medical mindset that will happen when genetically modified stem cells can change the care of chronic diseases from daily therapy to cures. Louis Bretton of Calimmune discussed how his company is trying to do this for HIV, which we blogged about yesterday when they announced promising first phase results from their first four patients. Faraz Ali of bluebird bio showed that his company has already made this life-changing shift for two patients with the blood disorder Beta Thalassemia. Like most patients with the disease they had been dependent on regular transfusions to survive, but when they received transplants of their own stem cells genetically modified to produce the correct version of a protein that is defective in the disease, they were able to live without transfusions.

The fourth panel provided proof that the field is maturing in that they discussed the many hurdles and pitfalls in taking those final steps to prepare a cell therapy to be a commercial product. The three big hurdles—financing, regulatory approval and reimbursement by insurers—all required creativity by the companies outlined in the two case studies. They are working through them but it is anything but a straightforward path. This is the area I hear the most hand wringing about in the halls of meetings in our field.

The last panel showed that one way around some of those end stage hurdles is to reach across borders. Four panelists discussed specific examples of ways international collaborations have accelerated their work toward developing therapies. CIRM has more than 20 collaborative agreements with funding agencies around the world, many of them painstakingly nurtured by our former president Alan Trounson. He gave the final presentation of the panel talking about one of his new projects, building an international stem cell bank with enough cell lines that almost everyone could get donor cells that were immunologically matched.

Our board chair, Jonathan Thomas, moderated the last panel and ended with a tribute to Alan noting that his build-out of our international program would be one of his many lasting legacies.
Don Gibbons

BIO International Panel Showed Stem Cell Science Poised to Make a Difference in Medical Practice Soon

When the biotechnology trade association began holding annual conferences in 1993, they drew 1,400 to the first event. This year BIO International expected nearly 20,000 here in San Diego. Among the dozens of concurrent sessions each day of this four-day scramble, stem cells got one track on one day this year. But listening to the progress being made by our presenters yesterday, our field is set to grow at the pace this meeting has—and could dominate the medical sessions here within the next decade.

995548_10151801308142804_405229409_n

After setting the scene with our opening panel yesterday, four subsequent panels confirmed the vast near-term potential painted by the opening speakers. They revealed a field maturing rapidly and starting to be a valued research tool of the bigger companies that have dominated the biotech industry, at the same time it is starting to deliver therapies to patients.

The second panel displayed the robust power of stem cells to model disease better than animal models ever could. These cells also let researchers dive much deeper into the genetic causes of disease, particularly diseases with multiple genes involved. Anne Bang from the Sanford-Burnham Institute mentioned her role in a consortium organized by the National Institutes of Health that is looking at the many genes involved in a type of heart weakening called left ventricular hypertrophy. Because different ethnicities tend to respond differently to drugs used for the condition, the consortium teams are creating iPS-type stem cell lines from 125 Caucasian patients and 125 African-American patients with various forms of the condition.

Their goal is to personalize and improve therapy across both patients groups. The way cells behave in the lab can tell the researchers much more relevant information than most animal models, so drugs developed based off their discoveries should have a better chance of success. All four panelists agreed that the field needs enough drugs developed with these tools to show that they do indeed have a better success rate. That track record should start to develop over the next few years.

The third panel talked about the shift in the medical mindset that will happen when genetically modified stem cells can change the care of chronic diseases from daily therapy to cures. Louis Bretton of Calimmune discussed how his company is trying to do this for HIV, which we blogged about yesterday when they announced promising first phase results from their first four patients. Faraz Ali of bluebird bio showed that his company has already made this life-changing shift for two patients with the blood disorder Beta Thalassemia. Like most patients with the disease they had been dependent on regular transfusions to survive, but when they received transplants of their own stem cells genetically modified to produce the correct version of a protein that is defective in the disease, they were able to live without transfusions.

The fourth panel provided proof that the field is maturing in that they discussed the many hurdles and pitfalls in taking those final steps to prepare a cell therapy to be a commercial product. The three big hurdles—financing, regulatory approval and reimbursement by insurers—all required creativity by the companies outlined in the two case studies. They are working through them but it is anything but a straightforward path. This is the area I hear the most hand wringing about in the halls of meetings in our field.

The last panel showed that one way around some of those end stage hurdles is to reach across borders. Four panelists discussed specific examples of ways international collaborations have accelerated their work toward developing therapies. CIRM has more than 20 collaborative agreements with funding agencies around the world, many of them painstakingly nurtured by our former president Alan Trounson. He gave the final presentation of the panel talking about one of his new projects, building an international stem cell bank with enough cell lines that almost everyone could get donor cells that were immunologically matched.

Our board chair, Jonathan Thomas, moderated the last panel and ended with a tribute to Alan noting that his build-out of our international program would be one of his many lasting legacies.
Don Gibbons

Stem Cell Stories that Caught our Eye: Speeding Stroke Recovery, HIV Clinical Trial, New Method for Growing Heart Cells

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Transplanting cells to speed stroke recovery. Stroke remains one of the most common forms of death and disability, yet utilization of therapies that can break down the blood clots that cause most forms of stroke lags; these therapies are only effective when used within 3 to 4 hours of the stroke but most patients arrive at the hospital too late. Now scientists from Shanghai Jiao Tong University may have a different solution that can repair damage already done.

Scientists have recently been looking to stem cell transplantation as a way to restore blood vessels or brain tissue destroyed by a stroke, but early experiments revealed limited effectiveness. In this study, which was published this week in Stem Cell Reports, the researchers coaxed embryonic stem cells further along in the development process before implanting them—which appears to have done the trick.

Using animal models, the team—led by Dr. Wei-Qiang Gao—transplanted two different types of so-called ‘precursor cells’ which have the ability to turn into the major types of brain and blood-vessel cells, the types of cells that are lost during a stroke.

Gao argues that this kind of transplantation is superior to previous methods because the two types of precursor cells can actually support each other in order to promote cell growth, and thus lays the foundation for new stem cell-based therapies to speed up recovery for stroke survivors.

CIRM-Funded Clinical Trial to Treat HIV. A team comprised of the City of Hope in Los Angeles, Sangamo Biosciences and the University of Southern California have developed an innovative approach to eradicating HIV.

With support from a CIRM grant, the researchers are developing a combination stem cell and gene therapy approach that is based on the success of the so-called “Berlin patient,” an HIV-positive man who was essentially cured after a bone-marrow transplant to treat his leukemia. In this instance, the bone marrow donor had a unique HIV-resistant mutation. The transplant transferred this mutation to the Berlin patient, and scientists have since been looking for a way to replicate this mutation on a larger scale. As explained in this week’s news release:

“Using an enzyme called a zinc-finger nuclease (ZFN), the research team can …“edit” the HIV patient’s stem cell genes so that, like the Berlin patient’s donor, they can no longer produce the protein. No protein, no HIV infection. The virus might then disappear from the body.

This study will be the first trial of ZFN technology in human stem cells. Earlier clinical studies in HIV-positive patients show that the ZFN method is generally safe when used with white blood cells called lymphocytes. And in one patient, the therapy was associated with temporary control of HIV without antiviral medication.”

The team hopes to begin testing this approach by the fall of 2014 on HIV patients who have not responded well to traditional therapies. CIRM funds a team that uses a different approach to gene editing that began a clinical trial last summer. You can read about both on our HIV fact sheet.

Building a Better Heart Cell. Stanford stem cell scientist Dr. Joseph Wu and his team have devised an improved method for generating large batches of heart muscle cells, known as cardiomyocytes, faster and cheaper than ever before. This new technique, described in the latest issue of Nature Methods, solves a long-standing problem in the field of regenerative medicine. As Wu explained in the Stanford University School of Medicine’s blog Scope:

“In order to fully realize the potential of these cells in drug screening and cell therapy, it’s necessary to be able to reliably generate large numbers at low cost….[Our] system is highly reproducible, massively scalable and substantially reduces costs to allow the production of billions of cardiomyocytes.”

This research, which was supported by a grant from CIRM, stands to improve scientists’ ability to use patient-derived cells not only to better understand how a heart becomes a heart, but also to test drugs that treat various types of heart disease.

The Great Divide: CIRM-Funded Research Resolves Controversy over the Regenerative Powers of Heart Cells

The human heart contains approximately 3 billion beating heart cells. But is this number predetermined from birth? Or do these cells have the ability to divide and replicate?

These questions have long dogged scientists—who initially thought that heart muscle cells, or cardiomyocytes, were incapable of dividing. But in recent years, new evidence came to light indicating that heart cells are, in fact, capable of regenerating. But how, or why, or even to what extent, remained a mystery.

MADAM, a new genetics-based approach to studying stem cells, can directly detect the moment that a heart cell divides.

MADAM, a new genetics-based approach to studying stem cells, can directly detect the moment that a heart cell divides.

Researchers employed a variety of techniques to try and answer this question—one group even tried carbon dating (a technique generally reserved for dating archaeological remains) to pinpoint the age of a human’s heart cells—but to no avail.

So Dr. Reza Ardehali and his team at UCLA’s Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research tried something new.

Published online recently in the Proceedings of the National Academy of Sciences, they developed a new genetics-based approach that could directly detect the moment that a heart cell divided. They called this technique the mosaic analysis with double markers, or MADAM.

Using the MADAM technique, the researchers observed in mouse models the timing and frequency by which heart cells grow and proliferate. In so doing, they found that—while rare after the first month of life—cardiomyocytes do divide within the heart in a symmetrical fashion. Specifically, the team measured a regeneration rate of just under one percent per year.

These findings, which were supported by a CIRM Grant, are essential for any future clinical studies into heart regeneration, as they can now take into account the existing regenerative capabilities of the heart. As Dr. Ardehali explained in the news release:

“This is a very exciting discovery because we hope to use this knowledge to eventually be able to regenerate heart tissue. The goal is to identify the molecular pathways involved in symmetric division of cardiomyocytes and use them to induce regeneration to replenish heart muscle tissue after disease or injury.”