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!)

CIRM Grantees Reflect on Ten Years of iPS Cells

For the fourth entry for our “Ten Years of Induced Pluripotent Stem (iPS) Cells” series, which we’ve been posting all month, I reached out to three of our CIRM grantees to get their perspectives on the impact of iPSC technology on their research and the regenerative medicine field as a whole:

granteesStep back in time for us to August 2006 when the landmark Takahashi/Yamanaka Cell paper was published which described the successful reprogramming of adult skin cells into an embryonic stem cell-like state, a.k.a. induced pluripotent stem (iPS) cells. What do you remember about your initial reactions to the study?

Sheng Ding, MD, PhD
Senior Investigator, Gladstone Institute of Cardiovascular Disease
Shinya had talked about the (incomplete) iPS cell work well before his 2006 publication in several occasions, so seeing the paper was not a total surprise.

Alysson Muotri, PhD
Associate Professor, UCSD Dept. of Pediatrics/Cellular & Molecular Medicine
At that time, I was a postdoc. I was in a meeting when Shinya first presented his findings. I think he did not give the identity of the 4 factors at that time. I was very excited but remember hearing rumors in the corridors saying the data was too good to be true. Soon after, the publication come out and it was a lot of fun reading it.

Joseph Wu, MD, PhD
Director, Stanford Cardiovascular Institute
I remember walking to the parking lot after work. One of my colleagues called me on my cell phone and he asked if I had seen “the Cell paper” published earlier that day. I said I haven’t and I would look it up when I get back home. I read it that night and found it quite interesting because the concept was simple but yet powerful.

How soon after the publication did you start using the iPSC technique in your own research? At that time, what research questions were you able to start exploring that weren’t possible in the “pre-iPS” era?

Ding:
I think many of us in the (pluripotent stem cell) field quickly jumped on this seminal discovery and started working on the iPSC technology itself as, at the time, there were many aspects of the discovery that would need to be better understood and further improved for its applications.

Muotri:
Immediately after the first mouse Cell paper, but I started with human cells. There were some concerns if the 4 factors will also work in humans. Nonetheless, I start using the mouse cDNA factors in human cells and it worked! I was amazed to witness the transformation and see the iPSC colonies in my dish – I showed the results to everyone in the lab.

Soon after, the papers showing that the procedure worked in human cells were published but I already knew that. Thus, I started to apply this to model disease, my main focus. In 2010, we published the modeling of the first neurodevelopmental disease using the iPSC technology. It is still a landmark publication, and I am very happy to be among the pioneers who believed in the Yamanaka technology.

Wu:
We started working on iPS cells about a couple of months after the initial publication. To our surprise, it was incredibly easy to reproduce, and we were able to get successful clones after a few initial attempts, in part because we had already been working on human embryonic stem (ES) cells for several years.

I think the biggest advantage of iPS cells is that we can know the medical record of the donor. So we can study the correlation between the donor’s underlying genetic makeup and their resulting cellular and whole-body characteristics using iPS cells as a platform for integrating these analyses. Examining these correlations is simply not possible with ES cells since no adult donor exists.

Dr. Ding, what do you think made you and your research team especially skilled at pioneering the use of small molecules to replace the “Yamanaka” reprogramming factors?

Ding:
We had been working on identifying and using small molecules to modulate stem cell fate (including cell proliferation, differentiation, and reprogramming) before iPS cell technology was reported. So when the iPS cell work was reported, it was obvious to us that we could apply our expertise in small molecule discovery to better understand and improve iPS cell reprogramming and replace the genetic factors by pharmacological approaches.

Now, come back to the present and reflect on how the paper has impacted your research over the past 10 years. Describe some of the key findings your lab has made over the past 10 years through iPSC studies

Ding:
We’ve worked on three aspects that are related to iPS cell research: one is to identify small molecule drugs that can functionally replace the genetic reprogramming factors, and enhance reprogramming efficiency and iPS cell quality (to mitigate risks associated with genetic manipulation, to make the iPS cell generation process more robust and efficient, and reduce the cost etc).

Second is to better understand the reprogramming mechanisms, that would allow us to improve reprogramming and better utilize cellular reprogramming technology. For example, we had uncovered and characterized several fundamental mechanisms underlying the reprogramming process.

The third is to “repurpose/re-direct” the iPS cell reprogramming into directly generating tissue/organ-specific precursor cells without generating iPS cell (itself, which is tumorigenic and needs to be differentiated for most of its applications). This so-called “Cell-Activation and Signaling-Directed/CASD” reprogramming approach allowed us to directly generate cells in the brain, heart, pancreas, liver, and blood vessels.

Muotri:
My lab has focused on the use of iPS cells to model autism spectrum disorder, a condition that is very heterogeneous both clinically and genetically. Previous models for autism, such as animals and postmortem tissues, were limited because we could not have access to live neurons to test experimentally several hypotheses. Thus, the attractiveness of the iPS cell model, by capturing the genome of patients in pluripotent stem cells and then guide them to become neural networks.

While the modeling in a dish was a great potential, there were some clear limitations too: the variability in the system was too high for example. My lab has worked hard to develop a chemically-defined culture media (iDEAL) to grow iPS cells and reduce the variability in the system. Moreover, we have developed robust protocols to analyze the morphology and electrophysiological properties of cortical neurons derived from iPS cells. We have used these methods to learn more about how genes impact neuronal networks and to screen drugs for several diseases.

We also used these methods to create cerebral organoids or “mini-brains” in a dish and have applied this technology to test the impact of several genetic and environmental factors. For example, we recently showed that the Zika virus could target neural progenitor cells in these organoids, leading to defects in the human developing cortex. Without this technology, we would be limited to mouse models that do not recapitulate the microcephaly of the babies born in Brazil.

Wu:
Our lab has taken advantage of the iPS cell platform to better understand cardiovascular diseases and to advance the precision medicine initiative. For example, we have used iPS cells to elucidate the molecular mechanisms of diseases related to an enlarged heart, cardiac arrhythmias, viral- and chemotherapy-induced heart disease, the genetics of coronary artery disease, among other diseases. We have also used iPS cells for testing the safety and efficacy of various cardiovascular drugs (i.e., “clinical trial in a dish”).

How are your findings important in terms of accelerating stem cell treatments to patients with unmet medical needs?

Ding:
Better understanding the reprogramming process and developing small molecule drugs for enhancing reprogramming would allow more effective generation of safe stem cells with reduced cost for treating diseases or doing research.

Muotri:
We work with two concepts. First, we screen drugs that could repair the disorder at a cellular level in a dish, hoping these drugs will be useful for a large fraction of autistic individuals. This approach can also be used to stratify the autistic population, finding subgroups that are more responsive to a particular drug. This strategy should help future clinical trials.

In parallel, we also work with the idea of personalized medicine by using patient-derived cells to create “disease in a dish” models in the lab. We then examine the genomic information of these cells to help us find drugs that are more specific to that individual. This approach should allow us to better design the treatment, testing ideal drugs and dosage, before prescribing it to the patient.

Wu:
The iPS cell technology provides us with an unprecedented glimpse into cardiovascular developmental biology. With this knowledge, we should be able to better understand how cardiac and vascular cells regenerate in the heart during different phases of human life and also during times of stress such as in the case of a heart attack. However, to be able to translate this knowledge into clinical care for patients will take a significant amount of time. This is because we still need to tackle the issues of immunogenicity, tumorigenicity, and safety for products that are derived from ES and iPS cells. Equally importantly, we need to understand how transplanted cells integrate into the patient because based on our experience so far, most of the injected cells die upon transplant into the heart. Finally, the economics of this type of personalized regenerative medicine is a daunting challenge.

Finally, it’s foolhardy to predict the future but, just for fun, imagine that I revisit you in August 2026. What key iPSC-related accomplishments do you think your lab will achieve by then?

Ding:
We are hoping to have cell-based therapy and small molecule drugs developed based on iPS cell-related research for treating human diseases. Particularly, we are also hoping our cellular reprogramming research would lead us to identify and develop small molecule drugs that control tissue/organ regeneration in vivo [in an animal].

Muotri:
We hope to have improved several steps on the neural differentiation, dramatically reducing costs and increasing efficiency.

Wu:
We would like to use the iPS cell platform to discover several new drugs (or repurpose existing drugs) for our cardiovascular patients; to replace the current industry standard of drug toxicity testing using the hERG assay (which I believe is outdated); to predict what medications patients should be taking (i.e., precision cardiovascular medicine); and to elucidate risk index of genetic variants (in combination with genome editing approach).

Stem cell stories that caught our eye: 3D mini-lungs, Parkinson’s culprit, Motherless babies!

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.

Mimicking human air sacs –  a new lab tool for studying respiratory disease
Studying a flat lawn of cells in a petri dish is so old fashioned these days. The current trend is to use stem cells to create mini-organs called organoids that more closely mimic the actual three dimensional structures that you would find in the human body. We’ve written about the creation of mini-brains, livers, pituitary glands and several other organoids. Now, a UCLA research team has added lung organoids to the list.

bioengineeredlung-liketissue_mid

3-D bioengineered lung-like tissue (left) resembles adult human lung (right).
Image credit: UCLA Broad Stem Cell Research Center

Reported yesterday in Stem Cells Translational Medicine, the CIRM-funded study describes the technique of nudging lung stem cells, collected from patients’ lung tissue, to self-assemble into 3D structures that resemble air sacs found in the human lung. This technique will surely usher in a better understanding of idiopathic pulmonary fibrosis, a disease that causes scarring of the lungs, leading to shortness of breath and depriving the organs of oxygen. The cause of the disease isn’t known in most cases and, sadly, people usually die within five years of their initial diagnosis.

One of the main challenges in the lab has been reproducing the tale tell scarring seen in this chronic lung disease. When lung cells are taken from pulmonary fibrosis patients and grown as a flat layer, the cells look healthy. But with this novel lung organoid technique, the researchers were able to manipulate the cells to develop the types of scars seen in actual diseased lungs. Better yet, the methodology is very straight-forward, as Dan Wilkinson described in a university press release:

“The technique is very simple. We can make thousands of reproducible pieces of tissue that resemble lung and contain patient-specific cells.”

Now the researchers are in a position to better understand the cellular and molecular basis of the disease and to test out possible treatments that would work best in each individual.

A common thread running through all Parkinson’s cases
The cause of Parkinson’s disease seems straight-forward enough: nerve cells that produce dopamine – a chemical signal that helps generate smooth body movements – progressively die leading to body stiffness, uncontrollable shaking in the limbs and weakened coordination, just to name a few symptoms.

But the underlying genetics of Parkinson’s is anything but simple. Mutations in several genes are associated with family histories of the disease while other mutations in other genes are known to indirectly increase the risk of developing Parkinson’s. These familial forms of Parkinson’s, however, only make up about 15% of all cases; the remaining are so-called sporadic, meaning there’s no obvious family history. So, treating Parkinson’s disease involves treating each of its many forms. But in a CIRM-funded study, published late last week in Cell Stem Cell, Stanford researchers reported on a common thread that appears to run through all forms of Parkinson’s disease.

The team focused on a known mutation in the LRRK2 gene, found in about 1 out of 20 cases of familial Parkinson’s and which pops up in 1 out of 50 cases of sporadic Parkinson’s. The link between LRRK2 and Parkinson’s had not been understood. The Stanford researchers found it plays an important role in the maintenance of mitochondria, structures that produce a cell’s energy needs.

constellation-the-morning-star

Oh, not that Miro’. We’re talking about the protein Miro!
(Image: www.joan-miro.net)

When mitochondria become damaged or old they begin spewing out molecules that are toxic to the cell. In response, the cell gobbles up these mitochondria but only after the LRRK protein interacts with and removes a protein called Miro which normally anchors the mitochondria to the cell’s internal structures. The mutated form of LRRK2 doesn’t interact with Miro very well and, as a result, Miro holds on to the toxic mitochondria which in turn are not dismantled as rapidly.

You’d think this mechanism of action would to be specific to the LRRK2-mutant Parkinson’s but to the scientists’ pleasant surprise, it wasn’t. They discovered this result by creating induced pluripotent stem cells from skin samples collected from twenty different subjects:  four healthy subjects; five with the sporadic Parkinson’s; six with familial Parkinson’s from LRRK2 mutations and five with familial patients from other mutations. The iPS cells were grown into dopamine-producing nerve cells, the kind that die off in Parkinson’s disease. With these cells in hand, they observed the impact of intentionally damaging the mitochondria.

As expected, this damage to the nerve cells from the healthy subjects led to the breakdown of Miro which in turn allowed the detachment and degradation of mitochondria. Also as expected, the nerve cells from patients with the LRRK2 mutant showed delays in the release and degradation of mitochondria. But when the team looked at the other Parkinson’s nerve cells not associated with the LRRK2 mutant, they found the same delay in the release of Miro and degradation of mitochondria.

This result points to Miro as a common player in all forms of Parkinson’s. Xinnan Wang, the team’s leader, spoke about the exciting implications of these findings in a university press release:

viewimage

Xinnan Wang

“Existing drugs for Parkinson’s largely work by supplying precursors that faltering dopaminergic nerve cells can easily convert to dopamine. But that doesn’t prevent those cells from dying, and once they’ve died you can’t bring them back. Measuring Miro levels in skin fibroblasts from people at risk of Parkinson’s might someday prove beneficial in getting an accurate, early diagnosis. And medicines that lower Miro levels could prove beneficial in treating the disease.” 

A cautionary tale about science communication
What to leave in, what to leave out: it’s the continual dilemma (I must add a fun dilemma) for a science writer. When writing for a general audience, if you describe a research report in too much detail you’re likely to quickly lose your reader. But not adding enough detail can lead the reader to draw conclusions that aren’t accurate. And just a like a game of telephone, as the story is passed along from one source to another, the resulting storyline has little resemblance to the original research.

Research published this week in Nature Communications provides a case in point. Many of news outlets that picked up the research story which involved the successful production of mouse pups from mixing sperm with an novel type of egg cell that had been induced to divide before fertilization. The resulting headlines suggested that scientists had identified an end run around the need for a female’s egg to produce offspring. Based on a quick glance at these condensed summaries of the research report, you’d think motherless babies were just around the corner.

Gretchen Vogel at Science Magazine wrote a terrific autopsy of this news story, describing in five steps how it took on a life of its own. It’s a humorous (I personally LOL’d when I read it) yet serious cautionary tale of how science communication can go awry. I highly recommended the short piece. For a sneak peek, here’s her “five easy steps to create a tabloid science headline”:

  1. vogel_

    Gretchen Vogel

    Take one jargon-filled paper title: “Mice produced by mitotic reprogramming of sperm injected into haploid parthenogenotes

  2. Distill its research into more accessible language. Text of Nature Communications press release: Mouse sperm injected into a modified, inactive embryo can generate healthy offspring, shows a paper in Nature CommunicationsAnd add a lively headline: “Mouse sperm generate viable offspring without fertilization in an egg
  3. Enlist an organization to invite London writers to a press briefing with paper’s authors.
    Headline of Science Media Centre press release: “Making embryos from a non-egg cell
  4. Have same group distribute a laudatory quote from well-known and respected scientist: 
    “[It’s] a technical tour de force.”
  5. Bake for 24 hours and present without additional reporting. Headline in The Telegraph: “Motherless babies possible as scientists create live offspring without need for female egg,” and in The Guardian: “Skin cells might be used instead of eggs to make embryos, scientists say.”

 

Making a deposit in the Bank: using stem cells from children with rare diseases to find new treatments

Part of The Stem Cellar series on ten years of iPS cells

chris-waters-580-by-388

For Chris Waters, the motivation behind her move from big pharmaceutical companies and biotech to starting a non-profit organization focused on rare diseases in children is simple: “What’s most important is empowering patient families and helping them accelerate research to the clinical solutions they so urgently need for their child ,” she says.

Chris is the founder of Rare Science. Their mission statement – Accelerating Cures for RARE Kids – bears a striking resemblance to ours here at CIRM, so creating a partnership between us just seemed to make sense. At least it did to Chris. And one thing you need to know about Chris, is that when she has an idea you should just get out of the way, because she is going to make it happen.

“The biggest gap in drug development is that we are not addressing the specific needs of children, especially those with rare diseases.  We need to focus on kids. They are our future. If it takes 14 years and $2 billion to get FDA approval for a new drug, how is that going to help the 35% of the 200 million children across the world that are dying before 5 years of age because they have a rare disease? That’s why we created Rare Science. How do we help kids right now, how do we help the families? How do we make change?”

Banking on CIRM for help

One of the changes she wanted to make was to add the blood and tissue samples from one of the rare disease patient communities she works with to the CIRM Induced Pluripotent Stem Cell Bank. This program is collecting samples from up to 3,000 Californians – some of them healthy, some suffering from diseases such as autism, Alzheimer’s, heart, lung and liver disease and blindness. The samples will be turned into iPS cells – pluripotent stem cells that have the ability to be turned into any other type of cell in the body – enabling researchers to study how the diseases progress, and hopefully leading to the development of new therapies.

 

lilly-grossman

Lilly Grossman: photo courtesy LA Times

Chris says many kids with rare diseases can struggle for years to get an accurate diagnosis and even when they do get one there is often nothing available to help them. She says one San Diego teenager, Lilly Grossman, was originally diagnosed with Cerebral Palsy and it took years to identify that the real cause of her problems was a mutation in a gene called ADCY5, leading to abnormal involuntary movement. At first Lily’s family felt they were the only ones facing this problem. They have since started a patient family organization (ADCY5.org) that supports others with this condition.

“Even though we know that the affected individuals have the gene mutation, we have no idea how the gene causes the observable traits that are widely variable across the individuals we know.  We need research tools to help us understand the biology of ADCY5 and other rare disease – it is not enough to just know the gene mutation. We always wanted to do a stem cell line that would help us get at these biological questions.”

Getting creative

But with little money to spend Chris faced what, for an ordinary person, might have been a series of daunting obstacles. She needed consent forms so that everyone donating tissue, particularly the children, knew exactly what was involved in giving samples and how those samples would be used in research.  She also needed materials to collect the samples. In addition she needed to find doctors and sites around the world where the families were located to help with the sample collection.  All of this was going to cost money, which for any non-profit is always in short supply.

So she went to work herself, creating a Research Participant’s Bill of Rights – a list of the rights that anyone taking part in medical research has. She developed forms explaining to children, teenagers and parents what happens if they give skin or blood samples as part of medical research, telling them how an individual’s personal medical health history may be used in research studies. And then she turned to medical supply companies and got them to donate the tubes and other materials that would be needed to collect and preserve the tissue and blood samples.

Even though ADCY5 is a very rare condition, Chris has collected samples from 42 individuals representing 13 different families, some affected with the condition as well as their unaffected siblings and parents. These samples come from families all around the world, from the US and Europe, to Canada and Australia.

“With CIRM we can build stem cell lines. We can lower the barrier of access for researchers who want to utilize these valuable stem cell lines that they may not have the resources to generate themselves.  The cell lines, in the hands of researchers, can potentially accelerate understanding of the biology. They can help us identify targets to focus on for therapies. They can help us screen currently approved medications or drugs, so we have something now that could help these kids now, not 14 years from now.”

The samples Chris collects will be made available to researchers not just here in the US, but around the world. Chris hopes this program will serve as a model for other rare diseases, creating stem cell lines from them to help close the gap between discovery research and clinical impact.

Rare bears for rare disease

But in everything she does, in the end it always comes down to the patient families. Chris says so many children and families battling a rare disease feel they are alone. So she created with her team, the RARE Bear program to let them know they aren’t alone, that they are part of a worldwide community of support. She says each bear is handmade by the RARE Bear Army which spans 9 countries including 45 states in the US.  Each RARE Bear is different, because “they are all one of a kind bears for one of a kind kids. And that’s why we are here, to help rare kids one bear at a time.”  The RARE Bear program, also helps with rare disease awareness, patient outreach and rare disease community building which is key for RARE Science Research Programs.

It’s working. Chris recently got this series of photos and notes from the parents of a young girl in England, after they got their bear.

“I wanted to say a huge heartfelt thank you for my daughters Rare bear. It arrived today to Essex, England & as you can see from my pictures Isabella loves her already! We have named her Faith as a reminder to never give up!”

Stem cell stories that caught our eye: improving heart care, fixing sickle cell disease, stem cells & sugar

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.

Using “disease in a dish” model to improve heart care
Medications we take to improve our quality of life might actually be putting our lives in danger. For example, some studies have shown that high doses of pain killers like ibuprofen can increase our risk of heart problems or stroke. Now a new study has found a way of using a person’s own cells, to make sure the drugs they are given help, and don’t hinder their recovery.

cardiacdisea

Cardiac muscle cells from boy with inherited heart arrhythmia.
Image: Emory University

Researchers at Emory University in Atlanta took skin cells from a teenage boy with an inherited heart arrhythmia, and turned them into induced pluripotent stem (iPS) cells – a kind of cell that can then be turned into any other cell in the body. They then turned the iPS cells into heart muscle cells and used those cells to test different medications to see which were most effective at treating the arrhythmia, without causing any toxic or dangerous side effects.

The study was published in Disease Models & Mechanisms. In a news release co-author Peter Fischbach, said the work enables them to study the impact on a heart cell, without taking any heart cells from patients:

“We were able to recapitulate in a petri dish what we had seen in the patient. The hope is that in the future, we will be able to do that in reverse order.”

Switching a gene “off” to ease sickle cell disease pain:
Sickle cell disease (SCD) is a nasty, inherited condition that not only leaves people in debilitating pain, but also shortens their lives. Now researchers at Dana-Farber and Boston Children’s Cancer and Blood Disorders Center have found a way that could help ease that pain in some patients.

SCD is caused by a mutation in hemoglobin, which helps carry oxygen around in our blood. The mutation causes normally soft, round blood cells to become stiff and sickle-shaped. These often stick together, blocking blood flow, causing intense pain, organ damage and even strokes.

In this study, published in the Journal of Clinical Investigation, researchers took advantage of the fact that SCD is milder in people whose red blood cells have a fetal form of hemoglobin, something which for most of us tails off after we are born. They found that by “switching off” a gene called BCL11A they could restart that fetal form of hemoglobin.

They did this in mice successfully. Senior author David Williams, in a story picked up by Health Medicine Network, says they now hope to try this in people:

“BCL11A represses fetal hemoglobin, which does not lead to sickling, and also activates beta hemoglobin, which is affected by the sickle-cell mutation. So when you knock BCL11A down, you simultaneously increase fetal hemoglobin and repress sickling hemoglobin, which is why we think this is the best approach to gene therapy in sickle cell disease.”

CIRM already has a similar approach in clinical trials. UCLA’s Don Kohn is using a genetic editing technique to add a novel therapeutic hemoglobin gene that blocks sickling of the red blood cells and hopefully cure the patient altogether. This fun video gives a quick summary of the clinical trial:


How a stem cell’s sugar metabolism controls its transformation potential
While CIRM makes its push to fund 50 more stem cell-based clinical trials by 2020, we also continue to fund research that helps us better understand stem cells. Case in point, this week a UCLA research team funded in part by CIRM reported that an embryonic stem cell’s sugar metabolism changes as its develops and that this difference has big implications on cell fate.

glucose

Glucose

The study, published in Cell Stem Cell, compared so-called “naïve” and “primed” human embryonic stem cells (ESCs). The naïve cells represent a very early stage of embryo development and the primed cells represent a slightly later stage. All cells use the sugar, glucose, to provide energy, though the researchers discovered that the naive stem cells “ate up” glucose four times faster than the primed stem cells (A fascinating side note is they also found the exact opposite behavior in mice: naïve mouse ESCs metabolize glucose slower than primed mouse ESCs. This is a nice example of why it’s important to study human cells to understand human biology). It turns out this difference effects each cells ability to differentiate, or specialize, into a mature cell type. When the researchers added a drug that inhibits glucose metabolism to the naïve cells and stimulated them down a brain cell fate, three times more of the cells specialized into nerve cells.

Their next steps are to understand exactly how the change in glucose metabolism affects differentiation. As Heather Christofk mentioned in a university press release, these findings could ultimately help researchers who are manipulating stem cells to develop cell therapy products:

“Our study proves that if you carefully alter the sugar metabolism of pluripotent stem cells, you can affect their fate. This could be very useful for regenerative medicine.”

CIRM jumped on the iPS cell bandwagon before it had wheels

Part of The Stem Cellar series on ten years of iPS cells

The first press release I issued that announced new research grants after arriving at CIRM in 2008 detailed 18 “New Cell Line” awards. Ten of those grants, announced in June that year, were for a type of stem cell that had not even been proven to exist until November the year before. Those induced pluripotent stem cells (iPS cells) so dramatically changed our field that their discovery led to the Nobel prize for Shinya Yamanaka just four years later.

Even though California voters approved the creation of CIRM in November 2004 and the agency’s first office opened just a few months later, the first grants for research projects did not get approved until February 2007. Litigation by opponents of stem cell research and the monumental task of setting up a granting agency from scratch resulted in a two-year gap between the vote and getting down to the business the voters resoundingly supported.

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One of the first videos we placed on CIRMTV on YouTube was on iPSCs

Those first research grants sought to increase the sparse number of California researchers actually doing research with human embryonic stem cells. But just eight months later, in October 2007, CIRM staff had enough confidence in the mettle of California’s researchers that they went to our Board with a concept proposal for the New Cell Line awards that included the option of developing human iPS cells. While Yamanaka had first reprogrammed mouse skin cells to iPS cells in 2006, at the time of the Board presentation it was only speculated to be possible with human tissue. Not until the following month did he and Wisconsin’s James Thomson simultaneous publish the creation of human iPS cells, which CIRM staff annotated into the New Cell Line Request for Applications before they posted it in December 2007.

Former colleague Uta Grieshammer managed the New Cell Line awards as a CIRM senior science officer. In a recent interview she said the scientific questions posed by those grants showed the value of these awards.

 “The types of research we ended up funding under this call reflected the breadth of the questions important to embryonic stem cell and iPS cell work.”

Those projects included:

  • Creating early stage embryonic stem cells (ESCs), called ICM stage, which had been done in mice but not humans;
  • creating “clinical grade” ESCs fit for use in patients;
  • creating ESCs from embryos discarded by families at IVF clinics because they carried mutations for inherited diseases with the goal of developing better models for those diseases;
  • creating iPS cells from people with diseases, also to develop better models of disease;
  • ways to make iPS cells that did not result in the reprogramming factors being integrated into the cell’s genes permanently, which could render them unfit for human therapy;
  • looking to see if the age of the adult cell used to make iPS cells matters in the resulting stem cell;
  • comparing iPS and ESC lines to see if they are truly equivalent.

Those all turned out to be critical questions for the field, many still dominating much of the research today.  One of the most robust areas of iPS research involves creating disease-in-a-dish models using patient-derived stem cells for diseases that have been historically difficult to model in animals. One of the New Cell Line grantees, Fred Gage at the Salk Institute in San Diego, became one of the first researchers anywhere to report physiological differences between nerves grown from normal individuals versus nerves grown from patients with mental health conditions.

uta-grieshammer “The excitement to me personally with the result of our New Cell Lines is access to understanding complex genetic diseases through iPS cells,” said Uta, who currently is helping us untangle even more complex diseases as part of the management team for California’s personalized medicine initiative.

Gage, along with a co-investigator at Johns Hopkins, just last week received a $15 million grant from the National Institutes of Health to screen drug libraries against iPS cell-derived nerves to look for treatments for schizophrenia and bi-polar disorder. Clearly the CIRM team was onto something back in 2007.

Footnote:  This will be my last regular post for The Stem Cellar. I will be retiring from CIRM later this month, though I may heed the call if my colleagues ask me to do a guest post from my new base on Cape Cod.

Stem cell stories that caught our eye: functioning liver tissue, making new bone, stem cells and mental health

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.

Functioning liver tissue. Scientists are looking to stem cells as a potential alternative treatment to liver transplantation for patients with end-stage liver disease. Efforts are still in their early stages but a study published this week in Stem Cells Translational Medicine, shows how a CIRM-funded team at the Children’s Hospital Los Angeles (CHLA) successfully generated partially functional liver tissue from mouse and human stem cells.

Biodegradable scaffold (left) and human tissue-engineered liver (right) (Photo courtesy of The Saban Research Institute at Children’s Hospital Los Angeles)

Biodegradable scaffold (left) and human tissue-engineered liver (right) (Photo courtesy of The Saban Research Institute at Children’s Hospital Los Angeles)

The lab had previously developed a protocol to make intestinal organoids from mouse and human stem cells. They were able to tweak the protocol to generate what they called liver organoid units and transplanted the tissue-engineered livers into mice. The transplants developed cells and structures found in normal healthy livers, but their organization was different – something that the authors said they would address in future experiments.

Impressively, when the tissue-engineered liver was transplanted into mice with liver failure, the transplants had some liver function and the liver cells in these transplants were able to grow and regenerate like in normal livers.

In a USC press release, Dr. Kasper Wang from CHLA and the Keck school of medicine at USC commented:

“A cellular therapy for liver disease would be a game-changer for many patients, particularly children with metabolic disorders. By demonstrating the ability to generate hepatocytes comparable to those in native liver, and to show that these cells are functional and proliferative, we’ve moved one step closer to that goal.”

 

Making new bone. Next up is a story about making new bone from stem cells. A group at UC San Diego published a study this week in the journal Science Advances detailing a new way to make bone forming cells called osteoblasts from human pluripotent stem cells.

Stem cell-derived osteoblasts (bone cells). Image credit Varghese lab/UCSD.

Stem cell-derived osteoblasts (bone cells). Image credit Varghese lab/UCSD.

One way that scientists can turn pluripotent stem cells into mature cells like bone is to culture the stem cells in a growth medium supplemented with small molecules that can influence the fate of the stem cells. The group discovered that by adding a single molecule called adenosine to the growth medium, the stem cells turned into osteoblasts that developed vascularized bone tissue.

When they transplanted the stem cell-derived osteoblasts into mice with bone defects, the transplanted cells developed new bone tissue and importantly didn’t develop tumors.

 In a UC newsroom release, senior author on the study and UC San Diego Bioengineering Professor Shyni Varghese concluded:

“It’s amazing that a single molecule can direct stem cell fate. We don’t need to use a cocktail of small molecules, growth factors or other supplements to create a population of bone cells from human pluripotent stem cells like induced pluripotent stem cells.”

 

Stem cells and mental health. Brad Fikes from the San Diego Union Tribune wrote a great article on a new academic-industry partnership whose goal is to use human stem cells to find new drugs for mental disorders. The project is funded by a $15.4 million grant from the National Institute of Mental Health.

Academic scientists, including Rusty Gage from the Salk Institute and Hongjun Song from Johns Hopkins University, are collaborating with pharmaceutical company Janssen and Cellular Dynamics International to develop induced pluripotent stem cells (iPSCs) from patients with mental disorders like bipolar disorder and schizophrenia. The scientists will generate brain cells from the iPSCs and then work with the companies to test for potential drugs that could be used to treat these disorders.

In the article, Fred Gage explained that the goal of this project will be used to help patients rather than generate data points:

Rusty Gage, Salk Institute.

Rusty Gage, Salk Institute.

“Gage said the stem cell project is focused on getting results that make a difference to patients, not simply piling up research information. Being able to replicate results is critical; Gage said. Recent studies have found that many research findings of potential therapies don’t hold up in clinical testing. This is not only frustrating to patients, but failed clinical trials are expensive, and must be paid for with successful drugs.”

“The future of this will require more patients, replication between labs, and standardization of the procedures used.”

Sneak Peak of our New Blog Series and the 10 Years of iPSCs Cell Symposium

New Blog Series

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Shinya Yamanaka

A decade has passed since Dr. Shinya Yamanaka and his colleagues discovered the Nobel Prize-winning technology called induced pluripotent stem cells (iPSCs). These stem cells can be derived from adult tissue and can develop into any cell type in the body. They are an extremely useful tool to model disease in a dish, screen for new drug therapeutics, and have the potential to replace lost or damaged tissue in humans.

In honor of this amazing scientific discovery, we’re launching a new blog series about iPSCs and their impact on CIRM since we started funding stem cell research in 2007. It will be a four-part series over the course of September ending with a blog highlighting the 10 Years of iPSCs Cell Symposium that will be hosted in Berkeley, CA in late September.

Here are the topics:

  • CIRM jumps on the iPSC bandwagon before it had wheels.
  • Expanding the CIRM iPSC bank, how individuals are making a difference.
  • Spotlight on CIRM-funded iPSC research, interviews with CIRM-funded scientists.
  • What the experts have to say, recap of the 10 Years of iPSCs Cell Symposium.

A Conference Dedicated to 10 Years of iPSCs

slide-2Cell Press is hosting a Symposium on September 25th dedicated to the 10th anniversary of Yamanaka’s iPSC discovery. The symposium is featuring famous scientists in biology, medicine, and industry and is sure to be one of the best stem cell conferences this year. The speakers will cover topics from discovery research to technology development and clinical applications of iPSCs.

More details about the Symposium can be found here.

Here are a few of the talks and events we’re excited about:

  • Keynote by Gladstone’s Shinya Yamanaka: Recent progress in iPSC research and application
  • Panel on ethical considerations for clinical translation of iPSC research
  • Organized run with Shinya Yamanaka (I can finally say that I’ve run with a Nobel Prize winner!)
  • Advances in modeling ALS with iPSCs by Kevin Eggan, Harvard University
  • Cellular reprogramming approaches for cardiovascular disease by Deepak Srivastava, Director of the Roddenberry (named after Star Trek’s Gene Roddenberry) Stem Cell Center at the Gladstone Institutes in San Francisco
  • Keynote by MIT’s Rudolf Jaenisch: Stem cells, iPSCs and the study of human development and disease

CIRM will be attending and covering the conference through our blog and on Twitter (@CIRMnews).

How many stem cell trials will it take to get a cure?

When I think about how many clinical trials it will take before a stem cell therapy is available to patients, I’m reminded of the decades old Tootsie Pop commercial where a kid asks a series of talking animals, “How many licks does it take to get to the Tootsie Roll center of a Tootsie Pop?”

While Mr. Cow, Mr. Fox, and Mr. Turtle are all stumped, Mr. Owl tackles the question like a true scientist:

“A good question. Let’s find out. [Takes Tootsie pop and starts licking]. A One…A Two-hoo…A Three-hee. [Insert loud crunching sounds] A Three!”

The commercial ends with the narrator concluding that the world may never know how many licks it takes to get to the center (because Mr. Owl failed to complete his experiment…not a true scientist after all).

What do Tootsie Pops have to do with stem cell therapies?

I’m not saying that the Tootsie Pop question holds the same level of importance as the question of when scientists will develop a stem cell therapy that cures a disease, but I find it representative of the confusion and uncertainty that the general public has about when the “promise of stem cell research” will become a reality.

Let me explain…

Mr. Owl claims that it only takes three licks to get to the center of a Tootsie Pop, but three licks obviously aren’t enough to get through the hard candy exterior to the chewy tootsie center. According to the Tootsie “Scientific Endeavors” page, “at least three detailed scientific studies” determined that it takes between 144-411 licks to get to the center. My intuition is to go with the scientists, but depending on how the experiment was conducted or maybe the size of the tongue used, the final answer could vary.

Embryonic stem cells

Embryonic stem cells

For stem cell clinical trials, the situation is similar. The first clinical trial approved in the U.S. using human embryonic stem cells was in 2009. Since then, hundreds of clinical trials have been conducted globally using pluripotent – either embryonic or induced pluripotent stem cells (iPSCs) – or adult stem cells. But so far, none have made their way routinely to patients outside of a clinical trial setting in the U.S., (although a few stem cell-based products have been approved in other countries), and it’s unclear how many more trials it will take to get to this point.

Part of this murkiness is because we’re still in the early days of stem cell research: human embryonic stem cells were first isolated by James Thomson in 1998, and iPSCs weren’t discovered by Shinya Yamanaka until 2006. Scientists need more time to conduct preclinical research to understand how these stem cells can be best used to treat certain diseases and what stem cells will do when transplanted into patients.

Another other issue is that the U.S. Food and Drug Administration (FDA) has only approved one stem cell therapy – cord blood stem cell transplantation – for commercial use in 2011 and none since then. A big debate is currently ongoing about whether the regulatory landscape needs to change so that stem cell treatments that show promise in trials can get to patients who desperately need them.

Hopefully soon, the FDA will adopt a more efficient strategy for approving stem cell therapies that still keeps patient safety at the forefront. Otherwise it could take a lot longer for newer stem cell technologies like iPSCs to make their way to the clinic (although we’ve seen some encouraging preliminary results using iPSC-based therapy in clinical trials for blindness).

Trial, trial, trial again

So how many clinical trials will it take for a stem cell therapy to succeed sufficiently to gain approval and when will that happen?

Unfortunately, we don’t know the answers to these questions, but we do know that scientists need to continue to develop and test new stem cell treatments in human trials if we want to see any progress.

At CIRM, we are currently funding 16 clinical trials involving stem cell therapies for cancer, heart failure, diabetes, spinal cord injury and other diseases. But we need to fund more trials to increase the odds that some will make it through the gauntlet and prove both safe and effective at treating patients. Our goal now is to fund 50 clinical trials in the next five years. It’s an aggressive plan, but one we feel will hopefully take stem cell therapies from promise to reality.

We also know that CIRM is a soldier in a large army of funding agencies, universities, companies, and scientists around the world battling against time to develop stem cell therapies that could help patients in their lifetimes. And with this stem cell army, we believe we’re getting closer to the chewy center of the Tootsie pop, or in this case, an approved stem cell therapy for patients desperate for a cure.

This blog was written as part of the CCRM Signals iPSC anniversary blog carnival. Please click here to read what other bloggers have to say about the future of stem cells and regenerative medicine.

Stem cell stories that caught our eye: Zika virus and adult brains, a step toward precision medicine and source of blood stem 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.

Zika virus and the adult brain.  While almost all the press attention for the Zika virus has centered on pregnant women and the devastating impact the virus can have on their developing babies, a few stories have noted that while most adults don’t know they have been infected, a few do. The one significant impact seen is a relatively rare incidence of Guillain-Barre Syndrome, which can cause temporary partial paralysis. That has triggered a few researchers to look for other impacts in adults infected with the mosquito-borne virus.

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Researchers trying to understand why the virus leads to the underdeveloped brains known as microcephaly, in infants have shown the virus does its nasty work at the level of the nerve stem cell. Although adults have far fewer nerve stem cells than a developing fetus, they do have some. So a team at Rockefeller University in New York and the La Jolla Institute for Allergy and Immunology decided to look for any effects of infection on adult nerve stem cells in mice.  They published the work this week in the journal Cell Stem Cell and report a dramatic reduction in adult nerve stem cells in infected mice.

“Adult neurogenesis is implicated in learning and memory,” said the La Jolla Institute’s Sujan Shresta in a press release from the journal. “We don’t know what this would mean in terms of human diseases, or if cognitive behaviors of an individual could be impacted after infection.”

Mice are normally resistant to Zika infection, so the researchers first had to genetically engineer mice to be susceptible to infection. That means several layer of caveats and more research are needed before any assertions about adult impact of Zika infection in humans.

This work captured considerable press attention including in Buzzfeed, NBC and USNews and World Report.

 

Heart felt precision medicine.  With the boost of a special initiative launched by the Obama administration, precision medicine is becoming all the rage, at least as a goal. While a few cancer therapies currently use this concept of matching therapies to a specific patient’s genetic makeup, few doctors outside of oncology can turn to similarly precise therapies.

Cardio cells image

Heart muscle cells

Work from a CIRM-funded team at Stanford has moved other doctors a bit closer to this goal for heart disease. But this research will not lead to treating it, rather it could allow doctors to prevent therapies used for other diseases from causing heart disease. Joseph Wu and his team have made two discoveries that help validate the use of the iPS reprogramming technique to make patient-specific stem cells and then mature them into heart muscle cells and see how those cells react to specific drugs.

“Thirty percent of drugs in clinical trials are eventually withdrawn due to safety concerns, which often involve adverse cardiac effects,” said Wu in a press release picked up by ScienceNewsLine. “This study shows that these cells serve as a functional readout to predict how a patient’s heart might respond to particular drug treatments and identify those who should avoid certain treatments.”

 

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Joseph Wu

There has always been some concern that the genetic manipulation used to create iPS cells changes the genetics of any adult tissue you make from the cells. So, with samples from three patients who were undergoing heart biopsy or transplant, which allowed harvesting mature heart muscle, the team compared the genetic signature of the adult heart muscle and that of heart muscle created from iPS cells.  They found no significant differences.

With skin samples from another seven subjects they created iPS cells and then heart muscle and compared their genetic signatures. The found some slight difference in all seven, but dramatic differences in one. That difference was in a genetic pathway involved in the inner workings of heart muscle. When they treated those cells with a diabetes drug that had been linked to heart problems, the cells reacted quite differently from the cells of the other six subjects treated with the same drug. With this knowledge a doctor could avoid ever choosing to put that particular patient on that diabetes drug.

 

Source of blood stem cells matters.  For years, bone marrow transplant—the one currently routine stem cell therapy—required digging into someone bone to harvest the stem cells. Over the decades that the procedure has been saving thousands of lives doctors have found less invasive methods to get the stem cells using drugs to “mobilize” the marrow stem cells and get them to move into the blood stream where they can be harvested.

While stem cell donors often find the new procedure a vast improvement, no one had done a thorough review of the outcomes for patients who receive stem cells gathered by the different procedures until a paper this week from the Fred Hutchison Cancer Research Center in Seattle. While they did not find any differences in overall life expectancy, they found vastly different outcomes in quality of life including psychological wellbeing and ability to return to work.

The Hutchison team attributed most of this difference to a lower rate of Graft Versus Host Disease (GVHD), possibly the most dangerous side effect of the procedure, which occurs when the stem cell transplant also contains adult immune system cells from the donor and those “graft” cells attack the “host,” the patient. It makes sense that when you harvest cells from the blood stream you would be more likely to also capture mature immune cells than when you harvest cells from marrow. And GVHD can be extremely painful, debilitating, and often deadly.

Stephanie Lee Hutchison

Stephanie Lee

“When both your disease and the recommended treatment are life-threatening, I don’t think people are necessarily asking ‘which treatment is going to give me better quality of life years from now?'” said Stephanie Lee the lead author in a press release from the cancer center. “Yet, if you’re going to make it through, as many patients do, you want to do it with good quality of life. That’s the whole point of having the transplant.”