Stem cell stories that caught our eye: Blood stem cells on a diet, Bladder control after spinal cord injuries, new ALS insights

Putting blood stem cells on a diet. (Karen Ring)


Valine. Image: BMRB

Scientists from Stanford and the University of Tokyo have figured out a new way to potentially make bone marrow transplants more safe. Published yesterday in the journal Science, the teams discovered that removing an essential amino acid, called valine, from the diets of mice depleted their blood stem cells and made it easier for them to receive bone marrow transplants from other mice without the need for radiation or chemotherapy. Removing valine from human blood stem cells yielded similar results suggesting that this therapeutic approach could potentially change and improve the way that certain cancer patients are treated.

In an interview with Science Magazine, senior author Satoshi Yamazaki explained how current bone marrow transplants are toxic to patients and that an alternative, safer form of treatment is needed.

“Bone marrow transplantation is a toxic therapy. We have to do it to treat diseases that would otherwise be fatal, but the quality of life afterward is often not good. Relative to chemotherapy or radiation, the toxicity of a diet deficient in valine seems to be much, much lower. Mice that have been irradiated look terrible. They can’t have babies and live for less than a year. But mice given a diet deficient in valine can have babies and will live a normal life span after transplantation.”

The scientists found that the effects of a valine-deficient diet were mostly specific to blood stem cells in the mice, but also did affect hair stem cells and some T cells. The effects on these other populations of cells were not as dramatic however as the effects on blood stem cells.

Going forward, the teams are interested to find out whether valine deficiency will be a useful treatment for leukemia stem cells, which are stem cells that give rise to a type of blood cancer. As mentioned before, this alternative form of treatment would be very valuable for certain cancer patients in comparison to the current regimen of radiation treatment before bone marrow transplantation.

Easing pain and improving bladder control in spinal cord injury (Kevin McCormack)
When most people think of spinal cord injuries (SCI) they focus on the inability to walk. But for people with those injuries there are many other complications such as intense nerve or neuropathic pain, and inability to control their bladder. A CIRM-funded study from researchers at UCSF may help point at a new way of addressing those problems.

The study, published in the journal Cell Stem Cell, zeroed in on the loss in people with SCI of a particular amino acid called GABA, which acts as a neurotransmitter in the central nervous system and inhibits nerve transmission in the brain, calming nervous activity.

Here’s where we move into alphabet soup, but stick with me. Previous studies showed that using cells called inhibitory interneuron precursors from the medial ganglionic eminence (MGE) helped boost GABA signaling in the brain and spinal cord. So the researchers turned some human embryonic stem cells (hESCs) into MGEs and transplanted those into the spinal cords of mice with SCI.

Six months after transplantation those cells had integrated into the mice’s spinal cord, and the mice not only showed improved bladder function but they also seemed to have less pain.

Now, it’s a long way from mice to men, and there’s a lot of work that has to be done to ensure that this is safe to try in people, but the researchers conclude: “Our findings, therefore, may have implications for the treatment of chronically spinal cord-injured patients.”

CIRM-funded study reveals potential new ALS drug target (Todd Dubnicoff)
Of the many diseases CIRM-funded researchers are tackling, Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s Disease, has got to be one of the worst.


Motor neurons derived from skin cells of a healthy donor
Image: UC San Diego

This neurodegenerative disorder attacks and kills motor neurons, the nerve cells that control voluntary muscle movement. People diagnosed with ALS, gradually lose the ability to move their limbs, to swallow and even to breathe. The disease is always fatal and people usually die within 3 to 5 years after initial diagnosis. There’s no cure for ALS mainly because scientists are still struggling to fully understand what causes it.

Stem cell-derived “disease in a dish” experiments have recently provided many insights into the underlying biology of ALS. In these studies, skin cells from ALS patients are reprogrammed into an embryonic stem cell-like state called induced pluripotent stem cells (iPSCS). These iPS cells are grown in petri dishes and then specialized into motor neurons, allowing researchers to carefully look for any defects in the cells.

This week, a UC San Diego research team using this disease in a dish strategy reported they had uncovered a cellular process that goes haywire in ALS cells. The researchers generated motor neurons from iPS cells that had been derived from the skin samples of ALS patients with hereditary forms of the disease as well as samples from healthy donors. The team then compared the activity of thousands of genes between the ALS and healthy motor neurons. They found that a particular hereditary mutation doesn’t just impair a protein called hnRNP A2/B1, it actually gives the protein new toxic activities that kill off the motor neurons.

Fernando Martinez, the first author on this study in Neuron, told the UC San Diego Health newsroom that these news results reveal an important context for their on-going development of therapeutics that target proteins like hnRNP:

“These … therapies [targeting hnRNP] can eliminate toxic proteins and treat disease. But this strategy is only viable if the proteins have gained new toxic functions through mutation, as we found here for hnRNP A2/B1 in these ALS cases.”

Eggciting News: Scientists developed fertilized eggs from mouse stem cells

A really eggciting science story came out early this week that’s received a lot of attention. Scientists in Japan reported in the journal Nature that they’ve generated egg cells from mouse stem cells, and these eggs could be fertilized and developed into living, breathing mice.

This is the first time that scientists have reported the successful development of egg cells in the lab outside of an animal. Many implications emerge from this research like gaining a better understanding of human development, generating egg cells from other types of mammals and even helping infertile women become pregnant.

Making eggs from pluripotent stem cells

The egg cells, also known as oocytes, were generated from mouse embryonic stem cells and induced pluripotent stem cells derived from mouse skin cells in a culture dish. Both stem cell types are pluripotent, meaning that they can generate almost any cell type in the human body.

After generating the egg cells, the scientists fertilized the eggs through in vitro fertilization (IVF) using sperm from a healthy male mouse. They allowed the fertilized eggs to grow into two cell embryos which they then transplanted into female mice. 11 out of 316 embryos (or 3.5%) produced offspring, which were then able to reproduce after they matured into adults.


These mice were born from artificial eggs that were made from stem cells in a dish. (K. Hayashi, Kyushu University)

Not perfect science

While impressive, this study did identify major issues with its egg-making technique. First, less than 5% of the embryos made from the stem-cell derived eggs developed into viable mice. Second, the scientists discovered that some of their lab-grown eggs (~18%) had abnormal numbers of chromosomes – an event that can prevent an embryo from developing or can cause genetic disorders in offspring.

Lastly, to generate mature egg cells, the scientists had to add cells taken from mouse embryos in pregnant mice to the culture dish. These outside cells acted as a support environment that helped the egg cells mature and were essential for their development. The scientists are working around this issue by developing artificial reagents that could hopefully replace the need for these cells.

Egg cells made from embryonic stem cells in a dish. (K. Hayashi, Kyushu University)

Egg cells made from embryonic stem cells in a dish. (K. Hayashi, Kyushu University)

Will human eggs be next?

A big discovery such as this one immediately raises ethical questions and concerns about whether scientists will attempt to generate artificial human egg cells in a dish. Such technology would be extremely valuable to women who do not have eggs or have problems getting pregnant. However, in the wrong hands, a lot could go wrong with this technology including the creation of genetically abnormal embryos.

In a Nature news release, Azim Surani who is well known in this area of research, said that these ethical issues should be discussed now and include the general public. “This is the right time to involve the wider public in these discussions, long before and in case the procedure becomes feasible in humans.”

In an interview with , James Adjaye, another expert from Heinrich Heine University in Germany, raised the point that even if we did generate artificial human eggs, “the final and ultimate test for fully functional human ‘eggs in a dish’ would be the fertilization using IVF, which is also ethically not allowed.”

Looking forward, senior author on the Nature study, Katsuhiko Hayashi, predicted that in a decade, lab-grown “oocyte-like” human eggs will be available but probably not at a scale for fertility treatments. Because of the technical issues his study revealed, he commented, “It is too preliminary to use artificial oocytes in the clinic.”

Stem cell stories that caught our eye: relief for jaw pain, vitamins for iPSCs and Alzheimer’s insights

Jaw bone stem cells may offer relief for suffers of painful joint disorder
An estimated 10 million people in the US – mostly women –  suffer from problems with their temporomandibular joint (TMJ) which sits between the jaw bone and skull. TMJ disorders can lead to a number of symptoms such as intense pain in the jaw, face and head; difficulty swallowing and talking; and dizziness.

ds00355_im00012_mcdc7_tmj_jpgThe TMJ is made up of fibrocartilage which, when healthy, acts as a cushion to enable a person to move their jaw smoothly. But this cartilage doesn’t have the capacity to heal or regenerate so treatments including surgery and pain killers only mask the symptoms without fixing the underlying damage of the joint.

Reporting this week in Nature Communications, researchers at Columbia University’s College of Dental Medicine identified stem cells within the TMJ that can form cartilage and bone – in cell culture studies as well as in animals. The research team further showed that the signaling activity of a protein called Wnt leads to a reduction of these fibrocartilage stem cells (FSCSs) in animals and as a result causes deterioration of cartilage. But injecting a known inhibitor of Wnt into the animals’ damaged TMJ spurred growth and healing of the joint.

The team is now in search of other Wnt inhibitors that could be used in a clinical setting. In a university press release, Jeremy Mao, a co-author on the paper, talked about the implications of these results:

“They suggest that molecular signals that govern stem cells may have therapeutic applications for cartilage and bone regeneration. Cartilage and certain bone defects are notoriously difficult to heal.”

Take your vitamins: good advice for people and iPS cells
From a young age, we’re repeatedly told how getting enough vitamins each day is important for a healthy life. Our bodies don’t produce these naturally occurring chemicals but they carry out critical biochemical activities to keep our cells and organs functioning properly.


Carrots: a great source of vitamin A. Image source: Wikimedia Commons

Well, it turns out that vitamins are also an important ingredient in stem cell research labs. Results published the Proceedings of the National Academy of Sciences (PNAS) this week by scientists in the UK and New Zealand show that vitamin A and C work together synergistically to improve the efficiency of reprogramming adult cells, like skin or blood, into the embryonic stem cell-like state of induced pluripotent stem cells (iPSCs).

By the time a stem cell has specialized into, let’s say, a skin cell, only skin cell-specific genes are active while others genes, like those needed for liver function, are shut down. Those non-skin genes are silenced through the attachment of chemical tags on the DNA, a process called methylation. It essentially provides the DNA with the means of maintaining a skin cell “memory”. To convert a skin cell back into a stem cell-like state, researchers in the lab must erase this “memory” by adding factors which demethylate, or remove the methylation tags on the silenced, non-skin related genes.

In the current research picked up by Science Daily, the researchers found that both vitamin A and C increase demethylation but in different ways. The study showed that vitamin A acts to increase the production of proteins that are important for demethylation while vitamin C acts to enhance the enzymatic activity of demethylation.

These insights may help add to the growing knowledge on how to most efficiently reprogram adult cells into iPSCs. And they may prove useful for a better understanding of certain cancers which contain cells that are essentially reprogrammed into a stem cell-like state.

New angles for dealing with the tangles in the Alzheimer’s brain
The memory loss and overall degradation of brain function seen in people with Alzheimer’s Disease (AD) is thought to be caused by the accumulation of amyloid and tau proteins which form plaques and tangles in the brain. These abnormal structures are toxic to brain cells and ultimately lead to cell death.

But other studies of post-mortem AD brains suggest a malfunction in endocytosis – a process of taking up and transporting proteins to different parts of the cell – may also play a role. While follow up studies corroborated this initial observation, they didn’t look at endocytosis in nerve cells so it remained unclear how much of a role it played in AD.

In a CIRM-funded study published this week in Cell Reports, UC San Diego researchers made nerve cells from human iPSCs and used the popular CRISPR and TALEN gene editing techniques to generate mutations seen in inherited forms of AD. One of those inherited mutations is in the PS1 gene which has been shown to play a role in transporting amyloid proteins in nerve cells. The research confirmed that this mutation as well as a mutation in the amyloid precursor protein (APP) led to a breakdown in the proper trafficking of APP within the mutated nerve cells. In fact, they found an accumulation of APP in a wrong area of the nerve cell. However, blocking the action of a protein called secretase that normally processes the APP protein helped restore proper protein transport. In a university press release, team leader Larry Goldstein, explained the importance of these findings:


Larry Goldstein.
Image: UCSD

“Our results further illuminate the complex processes involved in the degradation and decline of neurons, which is, of course, the essential characteristic and cause of AD. But beyond that, they point to a new target and therapy for a condition that currently has no proven treatment or cure.”



Using skin cells to repair damaged hearts


Heart muscle  cells derived from skin cells

When someone has a heart attack, getting treatment quickly can mean the difference between life and death. Every minute delay in getting help means more heart cells die, and that can have profound consequences. One study found that heart attack patients who underwent surgery to re-open blocked arteries within 60 minutes of arriving in the emergency room had a six times greater survival rate than people who had to wait more than 90 minutes for the same treatment.

Clearly a quick intervention can be life-saving, which means an approach that uses a patient’s own stem cells to treat a heart attack won’t work. It simply takes too long to harvest the healthy heart cells, grow them in the lab, and re-inject them into the patient. By then the damage is done.

Now a new study shows that an off-the-shelf approach, using donor stem cells, might be the most effective way to go. Scientists at Shinshu University in Japan, used heart muscle stem cells from one monkey, to repair the damaged hearts of five other monkeys.

In the study, published in the journal Nature, the researchers took skin cells from a macaque monkey, turned those cells into induced pluripotent stem cells (iPSCs), and then turned those cells into cardiomyocytes or heart muscle cells. They then transplanted those cardiomyocytes into five other monkeys who had experienced an induced heart attack.

After 3 months the transplanted monkeys showed no signs of rejection and their hearts showed improved ability to contract, meaning they were pumping blood around the body more powerfully and efficiently than before they got the cardiomyocytes.

It’s an encouraging sign but it comes with a few caveats. One is that the monkeys used were all chosen to be as close a genetic match to the donor monkey as possible. This reduced the risk that the animals would reject the transplanted cells. But when it comes to treating people, it may not be feasible to have a wide selection of heart stem cell therapies on hand at every emergency room to make sure they are a good genetic match to the patient.

The second caveat is that all the transplanted monkeys experienced an increase in arrhythmias or irregular heartbeats. However, Yuji Shiba, one of the researchers, told the website ResearchGate that he didn’t think this was a serious issue:

“Ventricular arrhythmia was induced by the transplantation, typically within the first four weeks. However, this post-transplant arrhythmia seems to be transient and non-lethal. All five recipients of [the stem cells] survived without any abnormal behaviour for 12 weeks, even during the arrhythmia. So I think we can manage this side effect in clinic.”

Even with the caveats, this study demonstrates the potential for a donor-based stem cell therapy to treat heart attacks. This supports an approach already being tested by Capricor in a CIRM-funded clinical trial. In this trial the company is using donor cells, derived from heart stem cells, to treat patients who developed heart failure after a heart attack. In early studies the cells appear to reduce scar tissue on the heart, promote blood vessel growth and improve heart function.

The study from Japan shows the possibilities of using a ready-made stem cell approach to helping repair damage caused by a heart attacks. We’re hoping Capricor will take it from a possibility, and turn it into a reality.

If you would like to read some recent blog posts about Capricor go here and here.

Stem Cell Experts Discuss the Ethical Implications of Translating iPSCs to the Clinic

Part of The Stem Cellar blog series on 10 years of iPSCs.

This year, scientists are celebrating the 10-year anniversary of Shinya Yamanaka’s Nobel Prize winning discovery of induced pluripotent stem cells (iPSCs). These are cells that are very similar biologically to embryonic stem cells and can develop into any cell in the body. iPSCs are very useful in scientific research for disease modeling, drug screening, and for potential cell therapy applications.

However, with any therapy that involves testing in human patients, there are ethical questions that scientists, companies, and policy makers must consider. Yesterday, a panel of stem cell and bioethics experts at the Cell Symposium 10 Years of iPSCs conference in Berkeley discussed the ethical issues surrounding the translation of iPSC research from the lab bench to clinical trials in patients.

The panel included Shinya Yamanaka (Gladstone Institutes), George Daley (Harvard University), Christine Mummery (Leiden University Medical Centre), Lorenz Studer (Memorial Sloan Kettering Cancer Center), Deepak Srivastava (Gladstone Institutes), and Bioethicist Hank Greely (Stanford University).

iPSC Ethics Panel

iPSC Ethics Panel at the 10 Years of iPSCs Conference

Below is a summary of what these experts had to say about questions ranging from the ethics of patient and donor consent, genetic modification of iPSCs, designer organs, and whether patients should pay to participate in clinical trials.

How should we address patient or donor consent regarding iPSC banking?

Multiple institutes including CIRM are developing iPSC banks that store thousands of patient-derived iPSC lines, which scientists can use to study disease and develop new therapies. These important cell lines wouldn’t exist without patients who consent to donate their cells or tissue. The first question posed to the panel was how to regulate the consent process.

Christine Mummery began by emphasizing that it’s essential that companies are able to license patient-derived iPSC lines so they don’t have to go back to the patient and inconvenience them by asking for additional samples to make new cell lines.

George Daley and Hank Greely discussed different options for improving the informed consent process. Daley mentioned that the International Society for Stem Cell Research (ISSCR) recently updated their informed consent guidelines and now provide adaptable informed consent templates that can be used for obtaining many type of materials for human stem cell research.  Daley also mentioned the move towards standardizing the informed consent process through a single video shared by multiple institutions.

Greely agreed that video could be a powerful way to connect with patients by using talented “explainers” to educate patients. But both Daley and Greely cautioned that it’s essential to make sure that patients understand what they are getting involved in when they donate their tissue.

Greely rounded up the conversation by reminding the audience that patients are giving the research field invaluable information so we should consider giving back in return. While we can’t and shouldn’t promise a cure, we can give back in other ways like recognizing the contributions of specific patients or disease communities.

Greely mentioned the resolution with Henrietta Lack’s family as a good example. For more than 60 years, scientists have used a cancer cell line called HeLa cells that were derived from the cervical cancer cells of a woman named Henrietta Lacks. Henrietta never gave consent for her cells to be used and her family had no clue that pieces of Henrietta were being studied around the world until years later.

In 2013, the NIH finally rectified this issue by requiring that researchers ask for permission to access Henrietta’s genomic data and to include the Lacks family in their publication acknowledgements.

Hank Greely, Stanford University

Hank Greely, Stanford University

“The Lacks family are quite proud and pleased that their mother, grandmother and great grandmother is being remembered, that they are consulted on various things,” said Hank Greely. “They aren’t making any direct money out of it but they are taking a great deal of pride in the recognition that their family is getting. I think that returning something to patients is a nice thing, and a human thing.”

What are the ethical issues surrounding genome editing of iPSCs?

The conversation quickly focused on the ongoing CRISPR patent battle between the Broad Institute, MIT and UC Berkeley. For those unfamiliar with the technique, CRISPR is a gene editing technology that allows you to cut and paste DNA at precise locations in the genome. CRISPR has many uses in research, but in the context of iPSCs, scientists are using CRISPR to remove disease-causing mutations in patient iPSCs.

George Daley expressed his worry about a potential fallout if the CRISPR battle goes a certain way. He commented, “It’s deeply concerning when such a fundamentally enabling platform technology could be restricted for future gene editing applications.”

The CRISPR patent battle began in 2012 and millions of dollars in legal fees have been spent since then. Hank Greely said that he can’t understand why the Institutes haven’t settled this case already as the costs will only continue to rise, but that it might not matter how the case turns out in the end:

“My guess is that this isn’t ultimately going to be important because people will quickly figure out ways to invent around the CRISPR/Cas9 technology. People have already done it around the Cas9 part and there will probably be ways to do the same thing for the CRISPR part.”

 Christine Mummery finished off with a final point about the potential risk of trying to correct disease causing mutations in patient iPSCs using CRISPR technology. She noted that it’s possible the correction may not lead to an improvement because of other disease-causing genetic mutations in the cells that the patient and their family are unaware of.

 Should patients or donors be paid for their cells and tissue?

Lorenz Studer said he would support patients being paid for donating samples as long as the payment is reasonable, the consent form is clear, and patients aren’t trying to make money off of the process.

Hank Greely said the big issue is with inducement and whether you are paying enough money to convince people to do something they shouldn’t or wouldn’t want to do. He said this issue comes up mainly around reproductive egg donation but not with obtaining simpler tissue samples like skin biopsies. Egg donors are given money because it’s an invasive procedure, but also because a political decision was made to compensate egg donors. Greely predicts the same thing is unlikely to happen with other cell and tissue types.

Christine Mummery’s opinion was that if a patient’s iPSCs are used by a drug company to produce new successful drugs, the patient should receive some form of compensation. But she said it’s hard to know how much to pay patients, and this question was left unanswered by the panel.

Should patients pay to participate in clinical trials?

George Daley said it’s hard to justify charging patients to participate in a Phase 1 clinical trial where the focus is on testing the safety of a therapy without any guarantee that there will be beneficial outcome to the patient. In this case, charging a patient money could raise their expectations and mislead them into thinking they will benefit from the treatment. It would also be unfair because only patients who can afford to pay would have access to trials. Ultimately, he concluded that making patients pay for an early stage trial would corrupt the informed consent process. However, he did say that there are certain, rare contexts that would be highly regulated where patients could pay to participate in trials in an ethical way.

Lorenz Studer said the issue is very challenging. He knows of patients who want to pay to be in trials for treatments they hope will work, but he also doesn’t think that patients should have to pay to be in early stage trials where their participation helps the progress of the therapy. He said the focus should be on enrolling the right patient groups in clinical trials and making sure patients are properly educated about the trial they are participating.

Thoughts on the ethics behind making designer organs from iPSCs?

Deepak Srivastava said that he thinks about this question all the time in reference to the heart:

Deepak Srivastava, Gladstone Institutes

Deepak Srivastava, Gladstone Institutes

“The heart is basically a pump. When we traditionally thought about whether we could make a human heart, we asked if we could make the same thing with the same shape and design. But in fact, that’s not necessarily the best design – it’s what evolution gave us. What we really need is a pump that’s electrically active. I think going forward, we should remove the constraint of the current design and just think about what would be the best functional structure to do it. But it is definitely messing with nature and what evolution has given us.”

Deepak also said that because every organ is different, different strategies should be used. In the case of the heart, it might be beneficial to convert existing heart tissue into beating heart cells using drugs rather than transplant iPSC-derived heart cells or tissue. For other organs like the pancreas, it is beneficial to transplant stem cell-derived cells. For diabetes, scientists have shown that injecting insulin secreting cells in multiple areas of the body is beneficial to Diabetes patients.

Hank Greely concluded that the big ethical issue of creating stem cell-derived organs is safety. “Biology isn’t the same as design,” Greely said. “It’s really, really complicated. When you put something into a biological organism, the chances that something odd will happen are extremely high. We have to be very careful to avoid making matters worse.”

For more on the 10 years of iPSCs conference, check out the #CSStemCell16 hashtag on twitter.

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?

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.

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.

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?

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

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.

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.

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?

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.

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.

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?

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].

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

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.


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.


Oh, not that Miro’. We’re talking about the protein Miro!

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:


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


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: 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 ( 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.


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.



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.”