Stem cell stories that caught our eye: three teams refine cell reprogramming, also stem cell tourism

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.

Why stem cells in the lab don’t grow up right. A classic cartoon among stem cell fans shows a stem cell telling a daughter cell it can grow up to become anything, and in a living creature that is pretty much true. But in the lab those daughter cells often don’t behave and mature properly. This seems particularly true for stem cells made by reprogramming adult cells through the iPS cell technology.

Tissues, such as heart muscle grown in the lab from stem cells too often look and behave like heart tissue found in a growing embryo rather than like a mature adult. A team at Johns Hopkins decided the best way to solve this problem was to understand the differences between those heart tissues maturing in a lab and those grown naturally and to understand those differences at the molecular level. They looked at which molecular and genetic signaling pathways were turned on in each during development.

After studying 17,000 genes in 200 heart cell samples they found that the pathways in the lab-grown cells were like a map in which the roads don’t line up. Pathways that were supposed to be turned on were not and ones that were supposed to be blocked were open. In a university press release picked up by they explain that they now intend to look for ways to correct some of those misguided cellular pathways, in part by making the lab conditions better mimic normal growing conditions.

The result should be tissues grown for research that result in a more accurate model of disease and, potentially, better tissue for transplantation and repair.

Getting the cells needed faster. Pretty much everyone’s cell therapy wish list contains cells that genetically match the patient—to reduce the chance of immune system rejection—and often with the added feature of genetic modification to correct an in-born error. We have the technology to do this. You can use the iPS cell system to reprogram a patient’s adult cells into stem cells and use any number of gene modifying tools to correct the error. But the combined processes can take three months or more; time patients often don’t have.

Researchers at the University of Wisconsin’s Morgridge Institute and the Murdoch Children’s Research Institute in Australia have sped up that process to just two weeks. They found a way to do the stem cell conversion and the genetic correction at the same time and used the trendy new gene-editing tool, CRISPR, which is faster and simpler than other methods. Wisconsin’s stem cell pioneer James Thompson commented on the work led by Sara Howden:

James Thompson

James Thompson

“If you want to conduct therapies using patient-specific iPS cells, the timeline makes it hard to accomplish. If you add correcting a genetic defect, it really looks like a non-starter. You have to make the cell line, characterize it, correct it, then differentiate it to the cells of interest. In this new approach, Dr. Howden succeeded in combining the reprogramming and the gene correction steps together using the new Cas9/CRISPR technology, greatly reducing the time required.”

Howden discussed the work with Australian Broadcasting Corp and her institute issued a press release. In the release she noted than when iPS-based therapies become a reality, the faster method will be critical for certain patients such as children with severe immune deficiency or people with rapidly deteriorating vision.

Skipping the stem cell step. A team at Guangzhou Medical University created unusually pure heart muscle cells directly from skin samples without first turning them into iPS type stem cells. This so-called “direct reprogramming” has been accomplished for a few years, but mostly in nerve tissue and with much less efficiency. This team got 80 percent pure heart muscle.

Heart muscle cells created with traditional iPS cell reprogramming

Heart muscle cells created with traditional iPS cell reprogramming

They also avoided one of the potential problems with iPS technology. Most often, the reprogramming happens using viruses to carry genetic factors into adult cells. The Chinese team used proteins to do the reprogramming, which are much less likely to leave lasting, and potentially cancer-causing, changes in the cells.

“While additional research is needed to fully understand the properties of these cells, the results suggest a potentially safer method to generate cardiac progenitor cells for use as a regenerative therapy after a heart attack,” said Anthony Atala, Editor-in-Chief of STEM CELLS Translational Medicine, which published the work and released a press release picked up by BioSpace.

The research team noted one bit of needed work that reflected back to the first item in this post. They need to see if the new heart cells function like mature native cells and can interact properly with native cells if transplanted.

Stemming stem cell tourism. A pair of medical ethicists, one from Rice University in Houston and one from Wake Forest University in North Carolina, published a call for reforms in how stem cell clinical trials are designed and regulated. They say our system should encourage people to get therapy in the U.S. at regulated clinics rather than go overseas or to seek out unproven therapies here.

“The current landscape of stem cell tourism should prompt a re-evaluation of current approaches to study cell-based interventions with respect to the design, initiation and conduct of U.S. clinical trials,” the authors wrote. “Stakeholders, including scientists, clinicians, regulators and patient advocates, need to work together to find a compromise to keep patients in the U.S. and within the clinical-trial process.”

The web portal MNT wrote an article on the paper based on a Rice press release. The piece notes that many of the same patients who came forward to secure state funding for stem cells like the voter initiative that created CIRM are now tired of waiting for therapies and are seeking out unproven therapies. The authors noted that the problems this causes, in addition to the risks for patients, include the lack of any systematic way to collect data on whether those therapies are really working.

“Policy should be aimed at bringing patients home and fostering responsible scientific research as well as access for patients,” they wrote. “This will require discussions about alternative approaches to the design and conduct of clinical trials as well as to how interventions are approved by the Food and Drug Administration.”

Bipolar Disorder-in-a-Dish: Game On for Finding New Drugs

Amy Winehouse: a tremendous talent lost to bipolar disorder. Credit: Wikimedia Commons

Amy Winehouse: a tremendous talent lost to bipolar disorder. Credit: Wikimedia Commons

The tragic path of biopolar disorder
Ernest Hemingway, Kurt Cobain, Amy Winehouse and Virginia Woolf – the world lost their creativity too soon. Each took their own life or succumbed to substance abuse, most likely due to their struggles with bipolar disorder. Also called manic depression, bipolar disorder is one of the most severe types of mental illness. It’s characterized by episodes of extreme manic behavior preceded or followed by bouts of devastating depression. Bipolar disorder is thought to affect 3-5% of the world’s population and, if left untreated, has a 15% risk of death by suicide.

Lithium is the most effective treatment for long term management of the disorder though the drug’s mechanism of action isn’t well understood. Sadly, many people who are bipolar don’t respond to lithium and instead must wade through a complex mix of drugs that attempts to tackle the varied symptoms.

Imaging studies suggest unique changes in the bipolar brain and studies of twins show a genetic component but scientists are far from unraveling the direct causes of bipolar disorder. Now, exciting research at the Salk Institute reported in Nature provides a powerful new tool for not only understanding the disease at a cellular level but also finding new drug treatments.

“The cells of these patients really are different”
Using induced pluripotent stem cell (iPSC) technology, the Salk team successfully grew nerve cells, or neurons, in the lab from skin samples of six people with bipolar disorder as well as from healthy individuals. When compared to the healthy neurons, the researchers saw a higher sensitivity of the bipolar neuron to stimuli. Jerome Mertens, a postdoctoral fellow and the lead author of the study, explained the result further in a Salk Institute press release:

“Neurons are normally activated by a stimuli and respond. The cells we have from all six patients are much more sensitive in that you don’t need to activate them very strongly to see a response.”

And Salk professor Rusty Gage, a CIRM grantee and the senior scientist of the study, points out that these cells represent a game-changer for the study of bipolar disorder:

“Researchers hadn’t all agreed that there was a cellular cause to bipolar disorder. So our study is important validation that the cells of these patients really are different.”

Lithium response in lab dish = lithium response in patients
And now comes the really exciting part. The team next studied the effects of lithium on these six bipolar patients’ cells. Three of the patients were responders to lithium treatment while the other three were not helped by the drug. When grown in lithium, the cells from the lithium responders became less sensitive, you might even say less “manic”, to stimuli while the cells from the lithium non-responders remained hyperactive.


Salk scientists discover cellular differences between brain cells from bipolar patients that respond to lithium and those that don’t. Neurons (white/red) from a subset of bipolar patients show changes in their electrical activity in response to lithium.Credit: Salk Institute

So the response of these “disease in a dish” cells to lithium corresponds perfectly with the lithium response in the patients. This result will undoubtedly propel the use of these iPSC-derived neurons to examine the causes of the diseases at a cellular and molecular level. Not only that but the cells should become a key resource for testing lithium alternatives that may help the portion of the bipolar population that doesn’t response to lithium.

In order words, this use of iPSC technology begins a new chapter in the effort to free sufferers from the life-long grip of bipolar disorder.

CIRM’s got skin in the game too
The incredible power of iPSCs to examine human disease like never before is not lost on the CIRM team. That’s why we’re so excited that our iPSC bank is now open for business. It’s a major effort by the agency to create a public stem cell bank developed from thousands of individuals. These cells will be available to scientists worldwide to better understand and to develop therapies for diseases of heart, lung and liver as well as neurodegenerative and childhood neurological disorders.

Related Links:
Seminar video: Carol Marchetto, Salk Institute staff scientist, discusses the study in greater detail 

Have Scientists Found a Stem Cell-lution to Thyroid Disorders?

The thyroid gland is located in the neck. (WebMD)

The thyroid gland is located in the neck. (WebMD)

Have you thanked your thyroid today? If not, you should because your thyroid is essential for many of life’s daily activities and processes that you probably take for granted.

You can thank your thyroid for things like regulating your body temperature and appetite, and keeping you energetic, slim, and focused. That’s because these small glands in your neck are hormone-producing factories, and thyroid secreted hormones (TSH) control the growth and development of our organs and tissues and regulate important processes like your metabolism.

When your thyroid doesn’t work…

People who have thyroid disorders suffer from a number of uncomfortable or even nasty symptoms. Those with overactive thyroid glands (hyperthyroidism) produce too much thyroid hormone and have an overactive metabolism, which causes symptoms such as excessive sweating, weight loss, heart problems, and sensitivity to heat. Those with underactive thyroids (hypothyroidism) don’t produce enough hormone and have an impaired metabolism, which causes symptoms of tiredness, reduced heart rate, hair loss, feeling cold, and weight gain.

There are other types of thyroid problems (cancer and inflammation to name a few), but the bottom line is that, if your thyroid isn’t functioning properly, your quality of life will be negatively affected.

A stem cell-lution to hypothyroidism

However, there maybe a new “stem cell-lution” therapy for some forms of thyroid dysfunction. Scientists from the Boston University School of Medicine and the Beth Israel Deaconess Medical Center reported in Cell Stem Cell on Thursday that they can generate functional thyroid tissue from stem cells derived from different mammalian models. This is a huge deal because previously, scientists were unable to manipulate pluripotent stem cells into mature thyroid cells that had the correct thyroid identity (meaning they turned on the correct combination of thyroid-specific genes). This previous inability has made it very difficult for scientists to model thyroid diseases in a dish.

In this study, the authors used two factors, BMP and FGF, to directly differentiate mouse pluripotent stem cells into thyroid progenitor cells. These progenitors could be coaxed further into mature and properly functioning thyroid organoids (3D thyroid-like structures) that secreted thyroid hormone both in a dish and when transplanted back into mice.

Scientists generated thyroid tissue from pluripotent stem cells of frogs, mice and humans. (Cell Stem Cell)

Scientists generated thyroid tissue from pluripotent stem cells of frogs, mice and humans. (Cell Stem Cell)

What was truly exciting about their discovery, was that the same two factors could make functional thyroid tissue from mouse, frog, and human pluripotent stem cells, showing that the role of BMP4 and FGF2 in thyroid development is conserved across multiple species.

With the bases loaded, the authors hit a grand slam by using BMP4 and FGF2 to generate thyroid progenitor cells from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) derived from the skin cells of both healthy individuals and patients with hypothyroidism.

Thyroid organoids generated from mouse embryonic stem cells. (Cell Stem Cell)

Thyroid organoids generated from mouse embryonic stem cells. (Cell Stem Cell)

Big Picture

This study not only offers a new understanding of the early stages of thyroid development, but provides a potential source of transplantable stem-cell derived thyroid progenitor cells for cell-based therapies that could treat some forms of hypothyroidism.

In a press release from the Beth Israel Deaconess Medical Center, co-senior author of the study Anthony Hollenberg explained the significance of their findings:

This research represents an important step toward the goal of being able to better treat thyroid diseases and being able to permanently rescue thyroid function through the transplantation of a patient’s own engineered pluripotent stem cells.


Co-senior author Darrell Kotton went further to describe the novelty of their discovery:

Until now, we haven’t fully understood the natural process that underlies early thyroid development. With this paper, we’ve identified the signaling pathways in thyroid cells that regulate their differentiation, the process by which unspecialized stem cells give rise to specialized cells during early fetal development.”


Remembering Anita Kurmann

Anita Kurmann

Anita Kurmann

While this discovery is a major step forward in the field of thyroid disease and regenerative medicine, the victory is bittersweet in light of the recent passing of the study’s first author, Anita Kurmann. Anita was a Swiss surgeon and a talented scientist who was tragically killed while riding her bike in Boston’s Back Bay on August 7th, 2015. She had just heard that her publication would be accepted to Cell Stem Cell days before the accident and was planning to start her own lab at the end of the year in Switzerland.

Her colleagues, friends, and the science world will miss her dearly. As a tribute to Anita, her co-authors dedicated the Cell Stem Cell publication to her memory.

We dedicate this work to the memory of our co-first author, Dr. Anita Kurmann, who died in a tragic bicycle accident when this manuscript was in the final stages of formatting. She was intelligent, well read, kind, humble, and tirelessly committed to her patients, her thyroid research, her family, and her colleagues, who miss her dearly.

Related Links:

CIRM Scholar Helen Fong on Stem Cells and Brain Disease

Helen Fong, CIRM Scholar and Research Scientist at the Gladstone Institutes

Helen Fong, CIRM Scholar and Research Scientist at the Gladstone Institutes

Meet another one of our talented CIRM Scholars, Helen Fong. She is currently a Research Scientist at the Gladstone Institutes and did her graduate work at the University of California, Irvine. Her passions include stem cells, disease modeling, and playing with differentiation protocols – the processes that tell stem cells to mature into specific tissues. As a CIRM Scholar, part of our educational training programs, Helen published four articles where she was listed as the first author. Her most recent one was a stellar study published in Stem Cell Reports using induced pluripotent stem cells (iPSCs) to model and understand a nerve cell-destroying brain disease called frontotemporal dementia.

We interviewed Helen to learn more about her work in stem cell research.

Q: What was your graduate school research on?

HF: I did my graduate work in the lab of Dr. Peter Donovan, who is a prominent germ cell and stem cell scientist, and was newly recruited to UCI when I began my studies. I was his first graduate student from UCI. Dr. Donovan’s research was focused on understanding the regulation of early human development using embryonic stem cells (ESCs) and how to improve human pluripotent stem cell culture. He was also interested in understanding the biological mechanisms that keep stem cells pluripotent (the ability to become all the other cell types in the body) and the genetic factors that are important for maintaining pluripotency. My graduate research was on understanding the basic biology of human ESCs. Specifically, I studied the role of the gene Sox2 in maintaining stem cell pluripotency and self renewal in human ESCs.

Q: What about your postdoctoral research?

HF: After my PhD, I decided to continue to work with stem cells because I knew that the field would continue to grow. There was still so much to be learned about these unique cells. I also genuinely enjoyed working with stem cells and couldn’t imagine not seeing them every day. I realized that I had a solid understanding of the basic biology of ESCs, but I wanted to use stem cells to study human disease. This ability is one of the huge selling points of working with human induced pluripotent stem cells (iPSCs) [which are created by reprogramming adult cells back to a pluripotent state]. The Gladstone Institutes was an excellent place to continue my training and to begin using iPSCs to understand neurological disease. I joined Dr. Yadong Huang’s lab in 2011 and am currently using human iPSCs to study brain degenerative diseases including frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and Alzheimer’s disease (AD).

My recent publication in Stem Cell Reports used human iPSCs from a patient with FTD as a model to understand the mechanisms behind this condition. This patient carried a rare genetic mutation in the MAPT gene called TAU-A152T. Several studies have reported a number of patients with this specific mutation that could put them at risk for developing FTD, PSP, and AD. However, it wasn’t clear what this mutation was doing to cause these disorders.

One of the ways you can study neurodegenerative diseases is using stem cells derived from patients harboring the disease causing mutations. We obtained human iPSCs made from the skin cells of a patient with FTD and this TAU mutation. I then used zinc finger nuclease (ZFN) genome editing technology to genetically correct the mutation back to the wild type (normal) sequence to see if removing this mutation in the patient iPSCs would generate healthier neurons (nerve cells) that don’t have symptoms of FTD. I was able to study the disease-causing effects of the TAU mutation by comparing healthy neurons I made from the corrected (normal) iPSC line to diseased neurons made from the TAU mutant iPSC line.

Neurons generated from FTD patient iPSCs. (Image courtesy of Helen Fong)

Neurons generated from FTD patient iPSCs. (Image courtesy of Helen Fong)

The neurons that I differentiated from the iPSCs carrying the TAU mutation showed an increase in TAU protein fragmentation [meaning the protein gets degraded and isn’t present in its normal form], an abnormal characteristic that can be associated with FTD and AD. We didn’t see this phenomenon in the neurons from the corrected (normal) human iPSCs, indicating that removal of this TAU mutation could improve the symptoms of these diseases. These results were exciting because we now had a culprit for what could be causing disease in these patients with this mutation. There is still much to be learned about the mechanisms of this mutation and the iPSCs have been an invaluable resource.

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

HF: CIRM has funded me for almost all of my stem cell training and research. I got my first CIRM training grant as a graduate student at UCI in 2006 and was funded for three years as a postdoc at the Gladstone. So I have CIRM to thank for all of my training.

When I first started out as a CIRM scholar, I believe I was part of one of their earlier pre-doctoral training grant programs. As the program expanded, I got to meet many of the other trainees at CIRM research conferences and interact with prominent stem cell scientists in the area. This was an incredible experience because I was exposed to stem cell research outside of my own institute, and I was able to meet all the big players in the field!

CIRM has also been very generous and provided me a travel allowance to attend any scientific conference of my choice. Over the years, I’ve gone to a lot of conferences nationally and internationally including ISSCR (International Society for Stem Cell Research), Keystone symposia, and the Society for Neuroscience (SfN). I have given scientific talks both at Keystone and SfN, and they proved to be excellent exposure for my work as well as a good place to get feedback. Another one of my favorite perks was the ability to purchase reagents for my own work at my own discretion, which gave me some freedom in dictating which direction I wanted my project to go. If I wanted to study a particular protein and needed a specific antibody to do that, I was able to get it with my CIRM funding.

Q: What’s next for your career?

HF: Currently, I am hoping to wrap up the project I am working on in the lab right now and generate a publication. I plan to continue to work on stem cells in the next step of my career and to work on challenging and cutting-edge projects. I feel fortunate for all the training and resources that I’ve received that got me to where I am today, and I hope to pass on many of my skills and knowledge to budding, young scientists.

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

HF: I really enjoy the fact that I have so much control over the fate of my stem cells. They have the ability to turn into almost any cell type, and we’ve developed so many protocols to guide them into the exact cell type we want. They don’t always behave, but I think figuring out the personality of each and every cell line is part of the fun.

Related Links:

From Stem Cells to Cures with Shinya Yamanaka and Google Ventures

How do you go from basic stem cell research to cures for patients? We ask this question everyday at CIRM, and we’re not alone in our tireless pursuit to find answers to this challenging question.

In fact, two leaders on different sides of the stem cell arena – research and investment – came together last week at the Gladstone Institutes’ Fall Symposium to discuss how stem cell research can be translated into effective cures.

Nobel prize winner, Dr. Shinya Yamanaka, and Google Ventures partner and Stanford PhD, Dr. Blake Byers, shared their thoughts on where stem cell research is now and the future of stem cell therapy for treating and curing disease.

iPS Cells and the Stem Cell Revolution

Gladstone President, Sandy Williams

Gladstone President, Sandy Williams

President of the Gladstone Institutes, Dr. Sandy Williams, laid the groundwork for the symposium by outlining ways that stem cell research, especially Dr. Yamanaka’s discovery of cellular reprogramming and induced pluripotent stem (iPS) cells, will lead to cures.

“Cellular reprogramming has really launched the stem cell revolution. There are three pathways that stem cell biology or cellular reprogramming can be turned into new medicines. Cellular transplantation, reprogramming cells inside the body, and cellular models of human disease created by cellular reprogramming are all different routes to cures.”

He followed with the point that the success of the stem cell revolution cannot rest solely on the shoulders of scientists and clinicians. He said, “the best science will never be a cure unless it passes into the commercial arena. It has to pass through venture investors, biotechnology companies, and pharmaceutical companies, device companies for scientific advances to help human beings.”

Yamanaka on iPS Cell Applications

Dr. Shinya Yamanaka

Dr. Shinya Yamanaka

Yamanaka covered the research side of the discussion and shared a heartwarming story about his father inspiring him to pursue medicine before delving into the applications of his Nobel prize winning technology.

After becoming a doctor, Yamanaka continued his training as a scientist, but not without significant hurdles to overcome before his career-defining success.

I had a clear vision, I wanted to help patients by doing medical research. But of course, it’s easy to say, but very difficult to achieve. I spent many hours, many days, and many years in laboratories without significant success. 20 years later however, I became extremely lucky to have a wonderful group of people. And that group developed a new technology. Our group was able to find a way to make a new type of stem cell, which we designated iPS cells.

He then discussed the power of iPS cell technology and how scientists can turn patient iPS cells into almost any cell type in the body. He also emphasized two major medical applications of iPS cells that will lead to cures.

iPS cells are very powerful. We can use these cells for two major medical applications. We can transplant healthy brain cells [derived from iPS cells] back into the patients brains to obtain functional recovery. This approach is known as regenerative medicine or cell therapy. We’ve been trying to apply this approach of cell therapy to many diseases and injuries, for example, eye diseases such as macular degeneration, brain diseases such as PD, and also spinal cord injury, heart failure, liver failure, and diabetes. Also we’ve been trying to make immune cells, or lymphocytes, that attack cancer cells from iPS cells as a new form of cancer therapy. This is the first medical application of iPS cells. Another yet equally important application of iPS cells is in drug discovery. Instead of transplanting back into patients, we can use iPS cells and brain cells or heart cells derived from iPS cells in laboratories at the universities, Gladstone Institutes, or pharmaceutical companies to make disease models to perform drug screening.

Yamanaka ended his speech with his big picture goal. “We really want to bring iPS cells to patients, and we really want to help patients by using iPS cells. Of course we still have a long long way to go, and we need to overcome many problems.”

Byers on Facing Stem Cell Hurdles Because It’s Worth it

On the investment and capital side, Blake Byers from Google Ventures discussed why stem cell research should be pursued even though the obstacles in our path to cures can be daunting.

Blake Byers, Google Ventures

Blake Byers, Google Ventures

While Byers has been on the “evil capitalist side of the world” for the past five years, he has been “taking soul supplements by continuing to do research at Stanford University.” His most recent scientific publication was published in July on generating dopaminergic neurons from human iPS cells and transplanting them into rats with Parkinson’s disease. Using a cutting-edge technology called optogenetics, Byers was able to manipulate the activity of these transplanted neurons in the rat brain using light and fiber optic cables. He said this experience was his “first foray into the power that stem cells have in a therapeutic capacity.”

He then explained why iPS cells show more promise as cures than other therapeutic avenues.

So why work with these stem cells if they are so much harder to work with than just a small molecule or some chemical that we bake up in the laboratory? The reason is because cells have something that none of these other molecules do. Cells have logic embedded into them. They have the ability to respond to their environment, integrate that response, and come up with their own intervention on our behalf. [With cells] we can start to think about things that biology doesn’t even do yet. So not only can we cure diseases as they arise, but we can start thinking about prevention of disease before it arises.

Byers then gave an example of how stem cells will benefit cancer therapy.

On the cancer side, we can take cells out of the body and train them to look for cancer, and then put them back in. They then go and hunt for those cancer cells and eradicate them. This work is being done by many labs. There’s a number of companies working on this strategy that are public companies that are valued in the billions, which gets capitalists like me very excited. And it’s just the beginning of a new field on the cancer side.

(For an example of this, see our just-approved clinical trail for glioblastoma)

Finally, Byers admitted that the stem cell field itself is far from putting stem cells and their derivatives into humans routinely, and that “there’s going to be lots of stuff that’s going to be difficult about this process. It’s going to be hard, but it will be worth it. So that means we should try to do this, and that’s the exact reason we are excited to be working in this field and very actively looking at companies in this general field of stem cells attempting to cure diseases.”

From Stem Cells to Cures

After listening to both Yamanaka and Byers, it was clear that both had the same view of the stem cell field. They both believe that we are at a turning point in stem cell research and that our efforts both at the bench and on the commercial side need to remain stalwart in their efforts to push stem cell research forward so we can develop safe and effective therapies for patients.

Blake Byers, Shinya Yamanaka, and Sandy Williams take questions from the audience.

Blake Byers, Shinya Yamanaka, and Sandy Williams take questions from the audience.

One comment from the audience that stood out was that the the main limitation to the success of stem cell research seems to be a reduction in funding at the very time we need to increase funding.

In response, Byers agreed and suggested that to fix the funding issue, there needs to be an objective function in stem cell research. He suggested that the field needs to “measure the output we are having and what the impact of it is.” He said what is currently lacking is an ability to “measure of that return on investment for society”.

Yamanaka followed up by addressing the issue of costs for cures. “The cost of new cures and medicines is extremely challenging but important. We now have many new medicines, but they are too expensive. How to lower those costs, [is a question] we seriously need to consider”.


Keeping elderly cells old to understand the aging process

Aging is a key risk factor for many diseases, particularly disorders of the brain like Alzheimer’s or Parkinson’s, which primarily occur in the elderly. So a better understanding of the aging process should provide a better understanding of these neurodegenerative diseases.

The induced pluripotent stem cell (iPSC) technique makes it possible to grow human brain cells, or neurons, in the lab from elderly patient skin samples. Unfortunately, this method has a major pitfall when it comes to aging research: reprogramming skin cells back into the embryonic stem cell-like state of iPSCs strips away many of their old age-related characteristics.

Based on data published last week in Cell Stem Cell, Salk Institute researchers used a different technique called direct reprogramming as a means to keep old cells old. This alternative method sidesteps the need to make iPSCs (which brings cells all the way back to the pluripotent state) and instead converts a skin cell directly into the desired cell type.

First author Jerome Mertens and senior author Rusty Gage (Courtesy of the Salk Institute for Biological Studies).

First author Jerome Mertens and senior author Rusty Gage (Courtesy of the Salk Institute for Biological Studies).

iPSC and direct reprogramming go head-to-head

The study, funded in part by CIRM, relied on skin samples from people ranging in age from newly born to 89 years. The team generated iPSC and iPSC-derived neurons from these samples. They also made so-called induced neurons (iNs) from the skin cells using the direct reprogramming method. Other CIRM grantees have pioneered direct reprogramming of skin into nerve cells (see link below).

Skin cell samples from elderly human donors are directly converted into induced neurons (iNs), shown. (image: Courtesy of the Salk Institute for Biological Studies)

Skin cells from elderly human donors are directly converted into induced neurons (iNs), shown. (Image courtesy of the Salk Institute for Biological Studies).

When comparing skin cells from donors younger than 40 years old versus cells from the over 40 group, the team found several genes had age-dependent activity patterns. Those differences virtually disappeared in the iPSCs and iPSC-derived neurons from the same individuals. However, unlike iPSCs, direct reprogramming of the skin cells to neurons (iNs) hung on to age-dependent differences in gene activity.

Loss of RanBP17 protein a fountain of youth in reverse

A deeper analysis identified one gene called RanBP17 whose activity levels declined with increased age of the donor in both the original skin cells and those directly converted into iNs. But when those same donor skin cells were turned into iPSCs or even iPSC-derived neurons, RanBP17 levels in the older cells were no longer reduced and were on par with RanBP17 levels in the younger cells. In follow up experiments, a reduction in RanBP17 protein led to glitches in the transport of proteins into the cell’s nucleus, which other studies have linked to neurodegenerative diseases as well as the aging process.


Gene expression patterns of age-related factors like RanBP17 are maintained in induced neurons but not iPSCs. (Mertens et al., 2015)

Altogether, these results encourage researchers to select iNs over iPSC-derived neurons when it comes to faithfully representing the aging process of brain cells. Based on a Salk Institute press release, you can tell that professor Martin Hezter, a contributing author, is excited about future studies with iNs:

By using this powerful approach, we can begin to answer many questions about the physiology and molecular machinery of human nerve cells–not just around healthy aging but pathological aging as well.


Related links:

The New World That iPS Cells Will Bring

A stem cell champion was crowned last month. Dr. Takahashi from the RIKEN center in Japan received the prestigious Ogawa-Yamanaka Prize for developing a human iPS cell therapy to treat a debilitating eye disease called macular degeneration. We wrote about the event held at the Gladstone Institutes in a previous blog and saved the juicy insights from Dr. Takahashi’s scientific presentation and her CIRM-exclusive interview for today.  We also put together a two minute video (see below) based on the interview with her as well as with Dr. Deepak Srivastava, Director of the Gladstone Institute of Cardiovascular Disease and Mr. Hiro Ogawa, a co-founder of the Ogawa-Yamanaka Prize.

Dawn of iPS Cells

As part of the ceremony, Dr. Takahashi gave a scientific talk on the “new world that iPS cells will bring”. She began with a historical overview of stem cell research, starting with embryonic stem cells and the immune rejection and ethical issues associated with their use. She then discussed Dr. Yamanaka’s game-changing discovery of iPS cells, which offered new strategies for disease modeling and potential treatments that avoid some of the issues can complicate embryonic stem cells.

Her excitement over this discovery was palpable as she explained how she immediately jumped into the iPS cell field and got her hands dirty. Knowing that this technology could have huge implications for regenerative medicine and the development of stem cell therapies, she made herself a seemingly unattainable promise. “I said to myself, I will apply iPS cells to humans within five years. And I became a woman of her words.”

An iPS cell world

Dr. Takahashi went on to tell her success story, and why she chose to develop an iPS cell therapy to treat a disease of blindess, age-related macular degeneration (AMD). She explained how AMD is a serious unmet medical need. The current treatment involves injections of an antibody that blocks the activity of a growth factor called VEGF. This factor causes an overgrowth of blood vessels in the eye, which does major damage to the cells in the retina and can cause blindness. This therapy however, is only useful for some forms of AMD not all.


Dr. Masayo Takahashi describing her team’s iPS-based therapy for macular degeneration during the inaugural ceremony for the Ogawa-Yamanaka Prize at The Gladstone Institutes.

She believed she could fix this problem by developing an iPS cell technology that would replace lost cells in the eye in AMD patients. To a captivated crowd, she described how she was able to generate a sheet of human iPS derived cells called retinal pigment epithelial (RPE) cells from a patient with AMD. This sheet was transplanted into the eye of the patient in the first ever iPS cell clinical trial. The transplant was successful and the patient had no adverse effects to the treatment.

While the clinical trial is currently on hold, Dr. Takahashi explained that she and her team learned a lot from this experience. They are currently pursuing additional safety measures for their iPS cell technology to make sure that the stem cell transplants will not cause cancer or other bad outcomes in humans.

Autologous vs. Allogeneic?

Another main topic in her speech, was the choice between using autologous (iPS cells made from a patient and transplanted back into the same patient) and allogeneic (iPS cells made from a donor and then transplanted into a patient) iPS cells for transplantation in humans. Dr. Tahakashi’s opinion was that autologous would be ideal, but not scaleable due to high costs and the amount of time it would take to make iPS cell lines for individual patients.


iPS cells reprogrammed from a woman’s skin. Blue shows nuclei. Green and red indicate proteins found in reprogrammed cells but not in skin cells (credit: Kathrin Plath / UCLA).

Her solution is to use an arsenal of allogeneic iPS cells that can be transplanted into patients without rejection by the immune system. This may be possible if both the donor and the patient share the same combination (called a “haplotype”) of cell surface proteins on their immune cells called human leukocyte antigens (HLA). She highlighted the work ongoing in Japan to generate a stock of HLA haplotype matched iPS cell lines that could be used for most of the Japanese population.

 Changing the regulatory landscape in Japan

It was clear from her talk that her prize winning accomplishments didn’t happen without a lot of blood, sweat, and tears both at the bench and in the regulatory arena. In a CIRM exclusive interview, Dr. Takahashi further explained how her pioneering efforts to bring iPS cells to patients helped revolutionize the regulatory landscape in Japan to make it faster and easier to test iPS cells in the clinic.

The power of iPS cells changed the Japanese [regulatory] law dramatically. We made a new chapter for regenerative medicine in pharmaceutical law. With that law, the steps are very quick for cell therapy. In the new chapter [of the law] … conditional approval will be given if you prove the safety of the cell [therapy]. It’s very difficult to show the efficacy completely in a statistical manner for regenerative medicine. So the law says we don’t have to prove the efficacy [of the therapy] thoroughly with thousands of patients. Only a small number of patients are needed for the conditional approval. That’s the big difference.”

We were curious about Dr. Takahashi’s involvement in getting these regulatory changes to pass, and learned that she played a significant role on the academic side to convince the Japanese ministry to change the laws.

This law was made in the cooperation with the ministry and academia. That was one thing that had never happened before. Academia means mainly the Japanese society for the regenerative medicine, and I’m a committee member of that. So we talked about the ideal law for regenerative medicine, and our society suggested various points to the ministry. And to our surprise, the ministry accepted almost all of the points and included them into the law. That was wonderful. Usually we are very conservative and slow in changing, but this time, I was amazed how quickly the law has been changed. It’s the power of iPS cells.”

The iPS cell future is now

As a champion stem cell scientist and a leader in regenerative medicine, Dr. Takahashi took the opportunity at the end of the event to emphasize that all scientists and clinicians in the iPS cell therapy field need to consider three things: develop safe protocols for generating iPS cells that become standard practice, understand the patient’s needs by focusing on how to benefit patients the most, and think of iPS cells as a treatment and consider the risk when developing these therapies.

The new world of iPS cells is opening doors onto uncharted territory, but Dr. Takahashi’s wise words provide a solid roadmap for the future success of iPS cell therapies.

Stem cell stories that caught our eye: new CRISPR fix for sickle cell disease, saving saliva stem cells, jumping genes in iPSCs and lung stem cells.

An end run around sickle cell disease with CRISPR
The CRISPR-based gene editing technique has got to be the hottest topic in biomedical research right now. And I sense we’re only at the tip of the iceberg with more applications of the technology popping up almost every week. Just two days ago, researchers at the Dana Farber Cancer Institute in Boston reported in Nature that they had identified a novel approach to correcting sickle cell disease (SCD) with CRISPR.

A mutation in the globlin gene leads to sickled red blood cells that clog up blood vessels

A mutation in the globlin gene leads to sickled red blood cells that clog up blood vessels (image: CIRM video)

Sickle cell anemia is a devastating blood disorder caused by a single, inherited DNA mutation in the adult form of the hemoglobin gene (which is responsible for making blood). A CIRM-funded team at UCLA is getting ready to start testing a therapy in clinical trials that uses a similar but different gene editing tool to correct this mutation. Rather than directly fixing the SCD mutation as the UCLA team is doing, the Dana Farber team focused on a protein called BCL11A. Acting like a molecular switch during development, BCL11A shifts hemoglobin production from a fetal to an adult form. The important point here is that the fetal form of hemoglobin can substitute for the adult form and is unaffected by the SCD mutation.

So using CRISPR gene editing, they deleted a section of DNA from a patient’s blood stem cells that reduced BCL11A and increased production of the fetal hemoglobin. This result suggests the technique can, to pardon the football expression, do an end run around the disease.

But if there’s already a recipe for directly fixing the SCD mutation, why bother with this alternate CRISPR DNA deletion method? In a press release Daniel Bauer, one of the project leaders, explains the rationale:

“It turns out that blood stem cells, the ultimate targets for this kind of therapy, are much more resistant to genetic repair than to genetic disruption.”

Whatever the case, we’re big believers in the need to have several shots on goal to help ensure a victory for patients.

Clinical trial asks: does sparing salivary stem cells protect against severe dry mouth?
I bet you rarely think about or appreciate your saliva. But many head and neck cancer patients who undergo radiation therapy develop severe dry mouth caused by damage to their salivary glands. It doesn’t sound like a big deal, but in reality, the effects of dry mouth are life-changing. A frequent need to drink water disrupts sleep and leads to chronic fatigue. And because saliva is crucial for preventing tooth decay, these patients often lose their teeth. Eating and speaking are also very difficult without saliva, which cause sufferers to retreat from society.

Help may now be on the way. On Wednesday, researchers from University of Groningen in the Netherlands reported in Science Translational Medicine the identification of stem cells in a specific region within the large salivary glands found near each ear. In animal experiments, the team showed that specifically irradiating the area where the salivary stem cells lie shuts down saliva production. And in humans, the amount of radiation to this area is linked to the severity of dry mouth symptoms.

Doctors have confirmed that focusing the radiation therapy beams can minimize exposure to the stem cell-rich regions in the salivary glands. And the research team has begun a double-blind clinical trial to see if this modified radiation treatment helps reduce the number of dry mouth sufferers. They’re looking to complete the trial in two to three years.

Keeping a Lid on Jumping Genes
Believe it or not, you have jumping genes in your cells. The scientific name for them is retrotransposons. They are segments of DNA that can literally change their location within your chromosomes.

While retrotransposons have some important benefits such as creating genetic diversity, the insertion or deletion of DNA sequences can be bad news for a cell. Such events can cause genetic mutations and chromosome instability, which can lead to an increased risk of cancer growth or cell death.

To make its jump, the DNA sequence of a retrotransposon is copied with the help of an intermediary RNA (the green object in the picture below). A special enzyme converts the RNA back into DNA and this new copy of the retrotransposon then gets inserted at a new spot in the cell’s chromosomes.

Retrotransposons: curious pieces of DNA that can be transcribed into RNA, copied into DNA, and inserted to a new spot in your chromosomes.

The duplication and insertion of transposons into our chromosomes can be bad news for a cell

Most of our cells keep this gene jumping activity in check by adding inhibitory chemical tags to the retrotransposon DNA sequence. Still, researchers have observed that in unspecialized cells, like induced pluripotent stem (iPS) cells, these inhibitory chemical tags are reduced significantly.

So you’d think that iPS cells would be prone to the negative consequences of retrotransposon reactivation and unleashed jumping genes. But in a CIRM-funded paper published on Monday in Nature Structural and Molecular Biology, UC Irvine researchers show that despite the absence of those inhibitory chemical tags, the retrotransposon activity is reduced due to the presence of microRNA (miRNA), in this case miRNA-128. This molecule binds and blocks the retrotransposon’s RNA intermediary so no duplicate jumping gene is made.

The team’s hope is that by using miRNA-128 to curb the frequency of gene jumping, they can reduce the potential for mutations and tumor growth in iPS cells, a key safety step for future iPS-based clinical trials.

Great hope for lung stem cells
Chronic lung disease is the third leading cause of death in the U.S. but sadly doctors don’t have many treatment options except for a full lung transplant, which is a very risky procedure with very limited sources of donated organs. For these reasons, there is great interest in better understanding the location and function of lung stem cells. Harnessing the regenerative abilities of these cells may lead to more alternatives for people with end stage lung disease.

In a BioMedicine Development commentary that’s geared for our scientist readers, UCSF researchers summarize the evidence for stem cell population in the lung. We’re proud to say that one of the lead authors, Matt Donne, is a former CIRM Scholar.

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The Ogawa-Yamanaka Prize Crowns Its First Stem Cell Champion

A world of dark

Imagine if you woke up one day and couldn’t see. Your life would change drastically, and you would have to painfully relearn how to function in a world that heavily relies on sight.

A retina of a patient with macular degeneration. (Photo credit: Paul Parker/SPL)

A retina of a patient with macular degeneration. (Photo credit: Paul Parker/SPL)

While most people don’t lose their sight overnight, many suffer from visual impairments that slowly happen over time. Glaucoma, cataracts, and macular degeneration are examples of debilitating eye diseases that eventually lead to blindness.

With almost 300 million people world wide with some form of visual impairment, there’s urgency in the scientific community to develop safe therapies for clinical applications. One of the most promising strategies is using human induced pluripotent stem (iPS) cells derived from patients to generate cell types suitable for transplantation into the human eye.

However, this task is more easily said than done. Safety, regulatory, and economical concerns make the process of translating iPS cell therapies from the bench into the clinic an enormous challenge worthy only of a true scientific champion.

A world of light

Dr. Masayo Takahashi

Dr. Masayo Takahashi

Meet Dr. Masayo Takahashi. She is a faculty member at the RIKEN Centre for Developmental Biology, a prominent female scientist in Japan, and a bona fide stem cell champion. Her mission is to cure diseases of blindness using iPS cell technology.

Since the Nobel Prize-winning discovery of iPS cells by Dr. Shinya Yamanaka eight years ago, Dr. Takahashi has made fast work using this technology to generate specific cells from human iPS cells that can be transplanted into patients to treat an eye disease called macular degeneration. This disease results in the degeneration of the retina, an area in the back of the eye that receives light and translates the information to your brain to produce sight.

Dr. Takahashi generates cells called retinal pigment epithelial (RPE) cells from human iPS cells that can replace lost or dying retinal cells when transplanted into patients with macular degeneration. What makes this therapy so exciting is that Dr. Takahashi’s iPS-derived RPE cells appear to be relatively safe and don’t cause an immune system reaction or cause tumors when transplanted into humans.

Because of the safety of her technology, and the unfulfilled needs of millions of patients with eye diseases, Dr. Takahashi made it her goal to take iPS cells into humans within five years of Dr. Yamanaka’s discovery.

Ogawa-Yamanaka Stem Cell Prize

It’s no surprise that Dr. Takahashi succeeded in her ambitious goal. Her cutting edge work has led to the first clinical trial using iPS cells in humans, specifically treating patients with macular degeneration. In September 2014, the first patient, a 70-year-old Japanese woman, received a transplant of her own iPS-derived RPE cells and no complications were reported.

Currently, the trial is on hold “as part of a safety validation step and in consideration of anticipated regulatory changes to iPS cell research in Japan” according to a Gladstone Institute news release. Nevertheless, this first iPS cell trial in humans has overcome significant regulatory hurdles, has set an important precedent for establishing the safety of stem cell therapies, and has given scientists hope that iPS cell therapies can become a reality.

Dr. Deepak Srivastava presents Dr. Takahashi with the Ogawa-Yamanaka Prize.

Dr. Deepak Srivastava presents Dr. Takahashi with the Ogawa-Yamanaka Prize.

For her accomplishments, Dr. Takahashi was recently awarded the first ever Ogawa-Yamanaka Stem Cell Prize and honored at a special event held at the Gladstone Institutes in San Francisco yesterday. This prize was established by a generous gift from Mr. Hiro Ogawa in collaboration with Dr. Shinya Yamanaka and Dr. Deepak Srivastava at the Gladstone Institutes. The award recognizes scientists who conduct translational iPS cell research that will eventually be applied to patients in the clinic.

In an interview with CIRM, Dr. Deepak Srivastava, the Director of the Gladstone Institute of Cardiovascular Disease and the Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, described the prestigious prize and the ceremony held at the Gladstone to honor Dr. Takahashi:

Dr. Deepak Srivastava

The Ogawa-Yamanaka prize prize is meant to incentivize and honor those whose work is advancing the translational use of stem cells for regenerative medicine. Dr. Masayo Takahashi is a pioneer in pushing the technology of iPS cell-derived cell types and actually introducing them into people. She’s the very first person in the world to successfully overcome all the regulatory barriers and the scientific barriers to introduce this new type of stem cell into a patient. And she’s done so for a condition of blindness called macular degeneration, which affects millions of people world wide, and for which there are very few treatments currently. We are honoring her with this prize for her pioneering efforts at making this technology one that can be applied to patients.

The new world that iPS cells will bring

As part of the ceremony, Dr. Takahashi gave a scientific talk on the new world that iPS cells will bring for patients with diseases that lack cures, including those with visual impairments. The Stem Cellar team was lucky enough to interview Dr. Takahashi as well as attend her lecture during the Gladstone ceremony. We will cover both her talk and her interview with CIRM in an upcoming blog.

The Stem Cellar team at CIRM was excited to attend this momentous occasion, and to know that CIRM-funding has supported many researchers in the field of iPS cell therapy and regenerative medicine. We would like to congratulate Dr. Takahashi on her impressive and impactful accomplishments in this area and look forward to seeing progress in iPS cell trial for macular degeneration.


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Brain Stem Cells in a Dish to the Rescue


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The best way to impress your friends at the next party you attend might be to casually mention that scientists can grow miniature brain models in a dish using human stem cells. Sure, that might scare away some people, but when you explain how these tiny brain models can be used to study many different neurological diseases and could help identify new therapies to treat these diseases, your social status could sky rocket.

Recently, a group at UC San Diego used human stem cells to model a rare neurological disorder and identified a drug molecule that might be able to fix it. This work was funded in part by CIRM, and it was published today in the journal Molecular Psychiatry.

The disorder is called MECP2 duplication syndrome. It’s caused by a duplication of the MECP2 gene located in the X chromosome, and is genetically inherited as an X-linked disorder, meaning the disease is much more common in males. Having extra copies of this gene causes a number of unfortunate symptoms including reduced muscle tone (hypotonia), intellectual disabilities, impaired speech, seizures, and developmental delays, to name a few. So far, treatments for this disorder only help ease the symptoms and do not cure the disease.

The group from UCSD decided to model this disease using induced pluripotent stem cells (iPSCs) derived from patients with MECP2 duplication syndrome. iPSCs can form any cell type in the body, and the group used this to their advantage by coaxing the iPSCs into the specific type of nerve cell affected by the disorder. Their hard work was rewarded when they observed that the diseased nerve cells acted differently than normal nerve cells without the disease.

In fact, the diseased nerve cells generated more connections with other nearby nerve cells, and this altered their ability to talk to each other and perform their normal functions. The senior author Alysson Muotri described the difference as an “over-synchronization of the neuronal networks”, meaning that they were more active and tended to fire their signals in unison.

After establishing a relevant nerve cell model of MECP2 duplication disorder, the group tested out a library of drug molecules and identified a new drug candidate that was able to rescue the diseased nerve cells from their “over-synchronized” activity.

The senior author Alysson Muotri commented on the study in a press release:

Alysson Muotri (Photo by David Ahntholz)  

This work is encouraging for several reasons. First, this compound had never before been considered a therapeutic alternative for neurological disorders. Second, the speed in which we were able to do this. With mouse models, this work would likely have taken years and results would not necessarily be useful for humans.


The press release goes on to describe how Muotri and his team plan to push their preclinical studies using human stem-cell based models forward in hopes of entering clinical trials in the near future.


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