Rare Disease Gets Big Boost from California’s Stem Cell Agency

UC Irvine’s Dr. Leslie Thompson and patient advocate Frances Saldana after the CIRM Board vote to approve funding for Huntington’s disease

If you were looking for a poster child for an unmet medical need Huntington’s disease (HD) would be high on the list. It’s a devastating disease that attacks the brain, steadily destroying the ability to control body movement and speech. It impairs thinking and often leads to dementia. It’s always fatal and there are no treatments that can stop or reverse the course of the disease. Today the Board of the California Institute for Regenerative Medicine (CIRM) voted to support a project that shows promise in changing that.

The Board voted to approve $6 million to enable Dr. Leslie Thompson and her team at the University of California, Irvine to do the late stage testing needed to apply to the US Food and Drug Administration for permission to start a clinical trial in people. The therapy involves transplanting stem cells that have been turned into neural stem cells which secrete a molecule called brain-derived neurotrophic factor (BDNF), which has been shown to promote the growth and improve the function of brain cells. The goal is to slow down the progression of this debilitating disease.

“Huntington’s disease affects around 30,000 people in the US and children born to parents with HD have a 50/50 chance of getting the disease themselves,” says Dr. Maria T. Millan, the President and CEO of CIRM. “We have supported Dr. Thompson’s work for a number of years, reflecting our commitment to helping the best science advance, and are hopeful today’s vote will take it a crucial step closer to a clinical trial.”

Another project supported by CIRM at an earlier stage of research was also given funding for a clinical trial.

The Board approved almost $12 million to support a clinical trial to help people undergoing a kidney transplant. Right now, there are around 100,000 people in the US waiting to get a kidney transplant. Even those fortunate enough to get one face a lifetime on immunosuppressive drugs to stop the body rejecting the new organ, drugs that increase the risk for infection, heart disease and diabetes.  

Dr. Everett Meyer, and his team at Stanford University, will use a combination of healthy donor stem cells and the patient’s own regulatory T cells (Tregs), to train the patient’s immune system to accept the transplanted kidney and eliminate the need for immunosuppressive drugs.

The initial group targeted in this clinical trial are people with what are called HLA-mismatched kidneys. This is where the donor and recipient do not share the same human leukocyte antigens (HLAs), proteins located on the surface of immune cells and other cells in the body. Around 50 percent of patients with HLA-mismatched transplants experience rejection of the organ.

In his application Dr. Meyer said they have a simple goal: “The goal is “one kidney for life” off drugs with safety for all patients. The overall health status of patients off immunosuppressive drugs will improve due to reduction in side effects associated with these drugs, and due to reduced graft loss afforded by tolerance induction that will prevent chronic rejection.”

Sequencing data helps us understand the genes involved in heart cell development

skin cells to beating heart

Human heart cells generated in the laboratory. Image courtesy of Nathan Palapant at the University of Queensland

Heart disease is the leading cause of death for both men and women in the United States and is estimated to be responsible for 31% of all deaths globally. This disease encompasses a wide variety of conditions that all effect how well your heart is able to pump blood to the rest of your body. One of the reasons that heart disease is so devastating is because, unlike many other organs in our bodies, heart tissue is not able to repair itself once it is damaged. Now scientists at the Institute for Molecular Bioscience at the University of Queensland and the Garvan Institute for Medical Research in Australia have conducted a tour de force study to exquisitely understand the genes involved in heart development.

The findings of the study are published in the journal Cell Stem Cell. in a press release, Dr. Nathan Palapant, one of the the lead authors, says this type of research could pay dividends for heart disease treatment because:

“We think the answers to heart repair almost certainly lie in understanding heart development. If we can get to grips with the complex choreography of how the heart builds itself in the first place, we’re well placed to find new approaches to helping it rebuild after damage.”

To determine which genes are involved in heart cell development, the investigators use a method called single cell RNA sequencing. This technique allowed them to measure how 17,000 genes (almost every gene that is active in the heart) were being turned on and off during various stages of heart cell development in 40,000 human pluripotent stem cells (stem cells that are capable of becoming any other cell type) experimentally induced to turn into heart cells.  This data set, the first of its kind, is a critical new resource for all scientists studying heart development and disease.

Interestingly, this study also addressed a commonly present, but rarely discussed issue with scientific studies: how applicable are results generated in vitro (in the lab) rather than the body, in the context of human health and disease? It is well known that heart cells generated in the lab do not have the exact same characteristics as mature heart cells found in our bodies, but the extent and precise nature of those discrepancies is not well understood. These scientists find that a gene called HOPX, which is one of earliest markers of heart cell development, is not always expressed when it should be during in vitro cardiac cell development, which, in turn, affects expression of other genes that are downstream of HOPX later on in development. Therefore, these scientists suggest that mis-expression of HOPX  might be one reason why in vitro heart cells express different genes and are distinct from heart cells in humans.

The scientists also learned that HOPX is responsible for controlling whether the developing heart cell moves past the “immature” dividing phase to the mature phase where cells grow bigger, but do not divide. This finding shows that this data set is powerful both for determining differences between laboratory grown cells versus mature human cells, but also provides critical biological information about heart cell development.

Joseph Powell, another lead author of this research, further explains how this work contributes to the important fundamentals of heart cell development:

“Each cell goes through its own series of complex, nuanced changes. They are all different, and changes in one cell affect the activity of other cells. By tracking those changes across the different stages of development, we can learn a huge amount about how different sub-types of heart cells are controlled, and how they work together to build the heart.”

How mice and zebrafish are unlocking clues to repairing damaged hearts

Bee-Gees

The Bee Gees, pioneers in trying to find ways to mend a broken heart. Photograph: Michael Ochs Archives

This may be the first time that the Australian pop group the Bee Gees have ever been featured in a blog about stem cell research, but in this case I think it’s appropriate. One of the Bee Gees biggest hits was “How can you mend a broken heart” and while it was a fine song, Barry and Robin Gibb (who wrote the song) never really came up with a viable answer.

Happily some researchers at the University of Southern California may succeed where Barry and Robin failed. In a study, published in the journal Nature Genetics, the USC team identify a gene that may help regenerate damaged heart tissue after a heart attack.

When babies are born they have a lot of a heart muscle cell called a mononuclear diploid cardiomyocyte or MNDCM for short. This cell type has powerful regenerative properties and so is able to rebuild heart muscle. However, as we get older we have less and less MNDCMs. By the time most of us are at an age where we are most likely to have a heart attack we are also most likely to have very few of these cells, and so have a limited ability to repair the damage.

Michaela Patterson, and her colleagues at USC, set out to find ways to change that. They found that in some adult mice less than 2 percent of their heart cells were MNDCMs, while other mice had a much higher percentage, around 10 percent. Not surprisingly the mice with the higher percentage of MNDCMs were better able to regenerate heart muscle after a heart attack or other injury.

So the USC team – with a little help from CIRM funding – dug a little deeper and did a genome-wide association study of these mice, that’s where they look at all the genetic variants in different individuals to see if they can spot common traits. They found one gene, Tnni3k, that seems to play a key role in generating MNDCMs.

Turning Tnni3K off in mice resulted in higher numbers of MNDCMs, increasing their ability to regenerate heart muscle. But when they activated Tnni3k in zebrafish it reduced the number of MNDCMs and impaired the fish’s ability to repair heart damage.

While it’s a long way from identifying something interesting in mice and zebrafish to seeing if it can be used to help people, Henry Sucov, the senior author on the study, says these findings represent an important first step in that direction:

“The activity of this gene, Tnni3k, can be modulated by small molecules, which could be developed into prescription drugs in the future. These small molecules could change the composition of the heart over time to contain more of these regenerative cells. This could improve the potential for regeneration in adult hearts, as a preventative strategy for those who may be at risk for heart failure.”

 

 

 

Family, faith and funding from CIRM inspire one patient to plan for his future

Caleb Sizemore speaks to the CIRM Board at the June 2017 ICOC meeting.

Having been to many conferences and meetings over the years I have found there is a really simple way to gauge if someone is a good speaker, if they have the attention of people in the room. You just look around and see how many people are on their phones or laptops, checking their email or the latest sports scores.

By that standard Caleb Sizemore is a spellbinding speaker.

Last month Caleb spoke to the CIRM Board about his experiences in a CIRM-funded clinical trial for Duchenne Muscular Dystrophy. As he talked no one in the room was on their phone. Laptops were closed. All eyes and ears were on him.

To say his talk was both deeply moving and inspiring is an understatement. I could go into more detail but it’s so much more powerful to hear it from  Caleb himself. His words are a reminder to everyone at CIRM why we do this work, and why we have to continue to do all that we can to live up to our mission statement and accelerate stem cell treatments to patients with unmet medical needs.

Video produced by Todd Dubnicoff/CIRM


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One day, scientists could grow the human cardiovascular system from stem cells

The human cardiovascular system is an intricate, complex network of blood vessels that include arteries, capillaries and veins. These structures distribute blood from the heart to all parts of the body, from our head to our toes, and back again.

This week, two groups of scientists published studies showing that they can create key components of the human cardiovascular system from human pluripotent stem cells. These technologies will not only be valuable for modeling the cardiovascular system, but also for developing transplantable tissues to treat patients with cardiovascular or vascular diseases.

Growing capillaries using 3D printers

Scientists from Rice University and the Baylor College of Medicine are using 3D printers to make functioning capillaries. These are tiny, thin vessels that transport blood from the arteries to the veins and facilitate the exchange of oxygen, nutrients and waste products between the blood and tissues. Capillaries are made of a single layer of endothelial cells stitched together by cell structures called tight junctions, which create an impenetrable barrier between the blood and the body.

In work published in the journal Biomaterials Science, the scientists discovered two materials that coax human stem cell-derived endothelial cells to develop into capillary-like structures. They found that adding mesenchymal stem cells to the process, improved the ability of the endothelial cells to form into the tube-like structures resembling capillaries. Lead author on the study, Gisele Calderon, explained their initial findings in an interview with Phys.org,

“We’ve confirmed that these cells have the capacity to form capillary-like structures, both in a natural material called fibrin and in a semisynthetic material called gelatin methacrylate, or GelMA. The GelMA finding is particularly interesting because it is something we can readily 3-D print for future tissue-engineering applications.”

Scientists grow capillaries from stem cells using 3D gels. (Image Credit: Jeff Fitlow/Rice University)

The team will use their 3D printing technology to develop more accurate models of human tissues and their vast network of capillaries. Their hope is that these 3D printed tissues could be used for more accurate drug testing and eventually as implantable tissues in the clinic. Co-senior author on the study, Jordan Miller, summarized potential future applications nicely.

“Ultimately, we’d like to 3D print with living cells … to create fully vascularized tissues for therapeutic applications. You could foresee using these 3D printed tissues to provide a more accurate representation of how our bodies will respond to a drug. The potential to build tissue constructs made from a particular patient represents the ultimate test bed for personalized medicine. We could screen dozens of potential drug cocktails on this type of generated tissue sample to identify candidates that will work best for that patient.”

Growing functioning arteries

In a separate study published in the journal PNAS, scientists from the University of Wisconsin-Madison and the Morgridge Institute reported that they can generate functional arterial endothelial cells, which are cells that line the insides of human arteries.

The team used a lab technique called single-cell RNA sequencing to identify important signaling factors that coax human pluripotent stem cells to develop into arterial endothelial cells. The scientists then used the CRISPR/Cas9 gene editing technology to develop arterial “reporter cell lines”, which light up like Christmas trees when candidate factors are successful at coaxing stem cells to develop into arterial endothelial cells.

Arterial endothelial cells derived from human pluripotent stem cells. (The Morgridge Institute for Research)

Using this two-pronged strategy, they generated cells that displayed many of the characteristic functions of arterial endothelial cells found in the body. Furthermore, when they transplanted these cells into mice that suffered a heart attack, the cells helped form new arteries and improved the survival rate of these mice significantly. Mice who received the transplanted cells had an 83% survival rate compared to untreated mice who only had a 33% survival rate.

In an interview with Genetic Engineering & Biotechnology News, senior author on the study James Thomson, explained the significance of their findings,

“Our ultimate goal is to apply this improved cell derivation process to the formation of functional arteries that can be used in cardiovascular surgery. This work provides valuable proof that we can eventually get a reliable source for functional arterial endothelial cells and make arteries that perform and behave like the real thing.”

In the future, the scientists have set their sights on developing a universal donor cell line that can treat large populations of patients without fear of immune rejection. With cardiovascular disease being the leading cause of death around the world, the demand for such a stem cell-based therapy is urgent.

Stem cell stories that caught our eye: two studies of the heart and cool stem cell art

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.

Image from Scope Blog.

Image from Scope Blog.

Understanding Heart Defects. Healthy heart tissue is made up of smooth, solid muscle, which is essential for normal heart function. Patients with a heart defect called left ventricular non-compaction (LVNC), lack normal heart tissue in their left ventricle – the largest, strongest blood-pumping chamber – and instead have spongy-looking tissue.

LVNC occurs during early heart development where pieces of heart muscle fail to condense (compact) and instead form an airy, sponge-like network that can leave patients at risk for heart failure and other complications.

A team at Stanford is interested in learning how LVNC occurs in humans, and they’re using human stem cells for the answer. Led by CIRM grantee Joe Wu, the scientists generated induced pluripotent stem cells (iPSCs) from four patients with LVNC. iPSCs are cells that can be turned into any other cell in the body, so Wu turned these cells into iPSC-derived heart muscle in a dish.

Wu’s team was particularly interested in determining why some LVNC patients have symptoms of disease while others seem perfectly normal. After studying the heart muscle cells derived from the four LVNC patients, they identified a genetic mutation in a gene called TBX20. This gene produces a type of protein called a cardiac transcription factor, which controls the expression of other heart related genes.

Upon further exploration, the scientists found that the genetic mutation in TBX20 prevented LVNC heart muscle cells from dividing at their normal rate. If they blocked the signal of mutant TBX20, the heart cells went back to their normal activity and created healthy looking heart tissue.

This study was published in Nature Cell Biology and covered by the Stanford Medicine Scope blog. In an interview with Scope, Joe Wu highlighted the big picture of their work:

Joseph Wu Stanford

Joseph Wu Stanford

“This study shows the feasibility of modeling such developmental defects using human tissue-specific cells, rather than relying on animal cells or animal models. It opens up an exciting new avenue for research into congenital heart disease that could help literally the youngest — in utero — patients.”

Stem Cell Heart Patch. Scientists from the University of Wisconsin, Madison are creating stem cell-based heart patches that they hope one day could be used to treat heart disease.

In a collaboration with Duke and the University of Alabama at Birmingham, they’re developing 3D stem cell-derived patches that contain the three main cell types found in the heart: cardiomyocytes (heart muscle cells), fibroblasts (support cells), and endothelial cells (cells that line the insides of blood vessels). These patches would be transplanted into heart disease patients to replace damaged heart tissue and improve heart function.

As with all research that has the potential for reaching human patients, the scientists must first determine whether the heart patches are safe in animal models. They plan to transplant the heart patches into a pig model – chosen because pigs have similar sized hearts compared to humans.

In a UW-Madison News release, the director of the UW-Madison Stem Cell and Regenerative Medicine Center Timothy Kamp, hinted at the potential for this technology to reach the clinic.

“The excitement here is we’re moving closer to patient applications. We’re at a stage when we need to see how these cells do in a large animal heart attack model. We’ll be making patches of heart muscle that can be applied to these injured areas.”

Kamp and his team still have a lot of work to do to perfect their heart patch technology, but they are thinking ahead. Two issues that they are trying to address are how to prevent a patient’s immune system from rejecting the heart patch transplant, and how to make sure the heart patches beat in sync with the heart they are transplanted into.

Check out the heart patches in action in this video:

(Video courtesy of Xiaojun Lian)

Cool Stem Cell Art! When I was a scientist, I worked with stem cells all the time. I grew them in cell culture dishes, coaxed them to differentiate into brain cells, and used a technique called immunostaining to take really beautiful, colorful pictures of my final cell products. I took probably thousands of pictures over my PhD and postdoc, but sadly, only a handful of these photos ever made it into journal publications. The rest collected dust either on my hard drive or in my lab notebook.

It’s really too bad that at the time I didn’t know about this awesome stem cell art contest called Cells I See run by the Centre for Commercialization of Regenerative Medicine (CCRM) in Ontario Canada and sponsored by the Stem Cell Network.

The contest “is about the beauty of stem cells and biomaterials, seen directly through the microscope or through the interpretive lens of the artist.” Scientists can submit their most prized stem cell images or art, and the winner receives a cash prize and major science-art street cred.

The submission deadline for this year’s contest was earlier this month, and you can check out the contenders on CCRM’s Facebook page. Even better, you can vote for your favorite image or art by liking the photo. The last date to vote is October 15th and the scientist whose image has the most likes will be the People’s Choice winner. CCRM will also crown a Grand Prize winner at the Till & McCulloch Stem Cell Meeting in October.

I’ll leave you with a few of my favorite photos, but please don’t let this bias your vote =)!

"Icy Astrocytes" by Samantha Yammine

“Icy Astrocytes” by Samantha Yammine (Vote here!)

"Reaching for organoids" by Amy Wong

“Reaching for organoids” by Amy Wong (Vote here!)

"Iris" by Sabiha Hacibekiroglu

“Iris” by Sabiha Hacibekiroglu (Vote here!)

Out of the mouths, or in this case hearts, of babes comes a hopeful therapy for heart attack patients

Pediatric-Congenital-Heart-Disease-patient-300x200

Lessons learned from babies with heart failure could now help adults

Inspiration can sometimes come from the most unexpected of places. For English researcher Stephen Westaby it came from seeing babies who had heart attacks bounce back and recover. It led Westaby to a new line of research that could offer hope to people who have had a heart attack.

Westaby, a researcher at the John Radcliffe hospital in Oxford, England, found that implanting a novel kind of stem cell in the hearts of people undergoing surgery following a heart attack had a surprisingly significant impact on their recovery.

Westaby got his inspiration from studies showing babies who had a heart attack and experienced scarring on their heart, were able to bounce back and, by the time they reached adolescence, had no scarring. He wondered if it was because the babies’ own heart stem cells were able to repair the damage.

Scarring is a common side effect of a heart attack and affects the ability of the heart to be able to pump blood efficiently around the body. As a result of that diminished pumping ability people have less energy, and are at increased risk of further heart problems. For years it was believed this scarring was irreversible. This study, published in the Journal of Cardiovascular Translational Research, suggests it may not be.

Westaby and his team implanted what they describe as a “novel mesenchymal precursor (iMP)” type of stem cell in the hearts of patients who were undergoing heart bypass surgery following a heart attack. The cells were placed in parts of the heart that showed sizeable scarring and poor blood flow.

Two years later the patients showed a 30 percent improvement in heart function, a 40 percent reduction in scar size, and a 70 percent improvement in quality of life.

In an interview with the UK Guardian newspaper, Westaby admitted he was not expecting such a clear cut benefit:

“Quite frankly it was a big surprise to find the area of scar in the damaged heart got smaller,”

Of course it has to be noted that the trial was small, only involving 11 patients. Nonetheless the findings are important and impressive. Westaby and his team now hope to do a much larger study.

CIRM is funding a clinical trial with Capricor that is taking a similar approach, using stem cells to rejuvenate the hearts of patients who have had heart attacks.

Fred Lesikar, one of the patient’s in the first phase of that trial, experienced a similar benefit to those in the English trial and told us about it in our Stories of Hope.

Spotlight on CIRM Grantee Joe Wu: Clinical Trials for Heart Disease in a Dish?

It’s always exciting to read a science article featuring a talented scientist who is breaking boundaries in the field of regenerative medicine. It’s especially exciting to us at CIRM when the scientist is a CIRM grantee.

Last week, OZY published a fun and inspiring piece on Stanford scientist Joe Wu. Dr. Wu is the Director of the Stanford Cardiovascular Institute and his lab studies how stem cells (both adult and pluripotent) function and how they can be used to model heart diseases and screen for new drug therapies. He also is a CIRM grantee and has a Disease Team Therapy Development grant that aims to clinically test human embryonic stem cell-derived cardiomyocytes (heart cells) in end stage heart failure patients.

Dr. Joe Wu. (Image Source: Sean Culligan/OZY)

Dr. Joe Wu. (Image Source: Sean Culligan/OZY)

The OZY piece does a great job of highlighting Dr. Wu’s recent efforts to use human induced pluripotent stem cells (iPS cells) to make heart tissue in a dish and model cardiovascular disease. And without getting too technical, the article explains Dr. Wu’s larger mission to combine precision medicine and stem cell research to identify drugs that would be best suited for specific patient populations.

The article commented,

“He envisions treatments based on an individual’s own iPS cells. For example, a popular breast cancer drug has an 8 percent chance of giving patients heart failure. In Wu’s world, we’d test the drug on stem cells first, and if a patient lands in that 8 percent, begin treatment for the side effects preemptively or avoiding the drug totally and avoiding heart failure, too.”

Basically, Dr. Wu sees the future of clinical trials in a dish using human stem cells. “His goal is to take these stem cells from thousands of patients to create a genetically diverse enough bank that will allow for “clinical trials in a dish” — Wu’s go-to phrase.”

Instead of following the traditional drug development paradigm that takes more than 10 years, billions of dollars, and unfortunately usually ends in failure, Dr. Wu wants to follow an accelerated path where stem cells are used for drug toxicity and efficacy testing.

This alternative path could improve overall drug development and approval by the FDA. The article explained,

“Testing drugs on stem cells will give big pharma and the FDA vastly improved heads up for toxic complications. Stem cells are “absolutely” the best avenue going forward, says Norman Stockbridge, director of the division of cardiovascular and renal products at the FDA’s Center for Drug Evaluation and Research.”

Not everyone is on the same page with Dr. Wu’s bold vision of the future of precision medicine, stem cells, and treatments for heart disease. Some believe he is overly ambitious, however top scientists in the stem cell field have praised Dr. Wu’s “systematic approach” to research and how he doesn’t stop at data discovery, he focuses on the big picture and how his work can ultimately help patients.

You can read more about Dr. Wu’s research on his lab website and I highly encourage you to check out the OZY article which is a great example of science communication for the general public.


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Rare disease underdogs come out on top at CIRM Board meeting

 

It seems like an oxymoron but one in ten Americans has a rare disease. With more than 7,000 known rare diseases it’s easy to see how each one could affect thousands of individuals and still be considered a rare or orphan condition.

Only 5% of rare diseases have FDA approved therapies

rare disease

(Source: Sermo)

People with rare diseases, and their families, consider themselves the underdogs of the medical world because they often have difficulty getting a proper diagnosis (most physicians have never come across many of these diseases and so don’t know how to identify them), and even when they do get a diagnosis they have limited treatment options, and those options they do have are often very expensive.  It’s no wonder these patients and their families feel isolated and alone.

Rare diseases affect more people than HIV and Cancer combined

Hopefully some will feel less isolated after yesterday’s CIRM Board meeting when several rare diseases were among the big winners, getting funding to tackle conditions such as ALS or Lou Gehrig’s disease, Severe Combined Immunodeficiency or SCID, Canavan disease, Tay-Sachs and Sandhoff disease. These all won awards under our Translation Research Program except for the SCID program which is a pre-clinical stage project.

As CIRM Board Chair Jonathan Thomas said in our news release, these awards have one purpose:

“The goal of our Translation program is to support the most promising stem cell-based projects and to help them accelerate that research out of the lab and into the real world, such as a clinical trial where they can be tested in people. The projects that our Board approved today are a great example of work that takes innovative approaches to developing new therapies for a wide variety of diseases.”

These awards are all for early-stage research projects, ones we hope will be successful and eventually move into clinical trials. One project approved yesterday is already in a clinical trial. Capricor Therapeutics was awarded $3.4 million to complete a combined Phase 1/2 clinical trial treating heart failure associated with Duchenne muscular dystrophy with its cardiosphere stem cell technology.  This same Capricor technology is being used in an ongoing CIRM-funded trial which aims to heal the scarring that occurs after a heart attack.

Duchenne muscular dystrophy (DMD) is a genetic disorder that is marked by progressive muscle degeneration and weakness. The symptoms usually start in early childhood, between ages 3 and 5, and the vast majority of cases are in boys. As the disease progresses it leads to heart failure, which typically leads to death before age 40.

The Capricor clinical trial hopes to treat that aspect of DMD, one that currently has no effective treatment.

As our President and CEO Randy Mills said in our news release:

Randy Mills, Stem Cell Agency President & CEO

Randy Mills, Stem Cell Agency President & CEO

“There can be nothing worse than for a parent to watch their child slowly lose a fight against a deadly disease. Many of the programs we are funding today are focused on helping find treatments for diseases that affect children, often in infancy. Because many of these diseases are rare there are limited treatment options for them, which makes it all the more important for CIRM to focus on targeting these unmet medical needs.”

Speaking on Rare Disease Day (you can read our blog about that here) Massachusetts Senator Karen Spilka said that “Rare diseases impact over 30 Million patients and caregivers in the United States alone.”

Hopefully the steps that the CIRM Board took yesterday will ultimately help ease the struggles of some of those families.

A cardiac love triangle: how transcription factors interact to make a heart

 Here’s a heartfelt science story for all those Valentine’s day fans out there. Scientists from the Gladstone Institutes have identified how a group of transcription factors interact during embryonic development to make a healthy heart. Their work will increase our biological understanding of how the heart is formed and could produce new methods for treating cardiovascular disease.

The study, published today in the journal Cell, describes a tumultuous love story between cardiac transcription factors. Transcription factors are proteins that orchestrate gene expression. They have the power to turn genes on or off by binding to specific DNA sequences and recruiting other proteins that will eventually turn the information encoded in that gene into a functional protein.

Every organ has its own special group of transcription factors that coordinate the gene expression required for that organ’s development. Often times, transcription factors within a group directly interact with each other and work together to conduct a specific sequence of events. These interactions are essential for making healthy tissues and organs, but scientists don’t always understand how these interactions work.

For the heart, scientists have already identified a group of transcription factors essential for cardiac development, and genetic mutations in any of these factors can impair heart formation and cause heart defects in newborns. What’s not known, however, are the details on how some of these cardiac transcription factors interact to get their job done.

A cardiac love triangle

In the Gladstone study, the scientists focused on how three key cardiac transcription factors – NKX2.5, TBX5, and GATA4 – interact during heart development. They first proved that these transcription factors are essential for the formation of the heart in mouse embryos. When they eliminated the presence of one of the three factors from the developing mouse embryo, they observed abnormal heart development and heart defects. When they removed two factors (NKX2.5 and TBX5), the results were even worse – the heart wasn’t able to form and none of the embryos survived.

Normal heart muscle cells, courtesy Kyoto University

Normal cardiomyocytes or heart cells, courtesy Kyoto University

Next, they studied how these transcription factors interact to coordinate gene expression in heart cells called cardiomyocytes made from mouse embryonic stem cells that lacked either NKX2.5, TBX5, or both of these factors. Compared to normal heart cells, cardiomyocytes that lacked one or both of these two transcription factors started beating at inappropriate times – either earlier or later than the normal heart cells.

Taking a closer look, the scientists discovered that TBX5, NKX2.5 and GATA4 all hangout in the same areas of the genome in embryonic stem cells that are transitioning into cardiomyocytes. In fact, each individual transcription factor required the presence of the others to bind their DNA targets. If one of these factors was missing and the love triangle was broken, the remaining transcription factors became confused and bound random DNA sequences in the genome, causing a mess by turning on genes that shouldn’t be on.

First author on the study, Luis Luna-Zurita, explained the importance of maintaining this cardiac love triangle in a Gladstone Press Release:

Luis Luna-Zurita, Gladstone Institute

Luis Luna-Zurita, Gladstone Institute

“Transcription factors have to stick together, or else the other one goes and gets into trouble. Not only are these transcription factors vital for turning on certain genes, but their interaction is important to keep each other from going to the wrong place and turning on a set of genes that doesn’t belong in a heart cell.”

Crystal structure tells all

Protein crystal structure of NKX2.5 and TBX5 bound to DNA.

Protein crystal structure of NKX2.5 and TBX5 bound to DNA. (Luna-Zurita et al. 2016)

The last part of the study proved that two of these factors, NKX2.5 and TBX5, directly interact and physically touch each other when they bind their DNA targets. In collaboration with a group from the European Molecular Biology Laboratory (EMBL) in Germany, they developed protein crystal structures to model the molecular structure of these transcription factors when they bind DNA.

Co-author and EMBL scientist Christoph Muller explained his findings:

“The crystal structure critically shows the interaction between two of the transcription factors and how they influence one another’s binding to a specific stretch of DNA. Our detailed structural analysis revealed a direct physical connection between TBX5 and NKX2-5 and demonstrated that DNA plays an active role in mediating the interaction between the two proteins.”

Big picture

While this study falls in the discovery research category, its findings increase our understanding of the steps required to make a healthy heart and sheds light on what goes wrong in patients or newborns with heart disease.

Senior author on the paper and Gladstone Professor Benoit Bruneau explained the biomedical applications of their study for treating human disease:

DSC_0281_2

Benoit Bruneau, Gladstone Institute

“Gene mutations that cause congenital heart disease lower the levels of these transcription factors by half, and we’ve shown that the dosage of these factors determines which genes are turned on or off in a cell. Other genetic variants that cause heart defects like arrhythmias also affect the function of these factors. Therefore, the better we understand these transcription factors, the closer we’ll come to a treatment for heart disease. Our colleagues at Gladstone are using this knowledge to search for small molecules that can affect gene regulation and reverse some of the problems caused by the loss of these transcription factors.”

 

I think it’s worth mentioning that these studies were done using mouse embryos and mouse embryonic stem cells. Future work should be done to determine whether this cardiac love triangle and the same transcription factor interactions exist in human heart cells.


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