Has the promise of stem cells been overstated?

One of the most famous stem cell scientists in the world said on Monday that the promise of stem cell treatments has in some ways been overstated.

In an interview with the New York Times, Dr. Shinya Yamanaka, one of the recipients of the 2012 Nobel Prize in Medicine for his discovery of induced pluripotent stem cells (iPS cells), said, “we can help just a small portion of patients by stem cell therapy.”

Shinya Yamanaka. (Image source: Ko Sasaki, New York Times)

Shinya Yamanaka. (Image source: Ko Sasaki, New York Times)

He explained that there are only 10 target diseases that he believes will benefit directly from stem cell therapies including, “Parkinson’s, retinal and corneal diseases, heart and liver failure, diabetes, spinal cord injury, joint disorders and some blood disorders. But maybe that’s all. The number of human diseases is enormous.”

This is a big statement coming from a key opinion leader in the field of stem cell research, and it’s likely to spur a larger conversation on the future of stem cell treatments.

Yamanaka also touched on another major point in his interview – progress takes time.

In the ten years since his discovery of iPS cells, he and other scientists have learned the hard way that the development of stem cell treatments can be time consuming. While autologous iPS cell treatments (making stem cell lines from a patient and transplanting them back into that patient) have entered clinical trials to treat patients with macular degeneration, a disease that causes blindness, the trials have been put on hold until the safety of the stem cell lines being used are confirmed.

At the World Alliance Forum in November, Yamanaka revealed that generating a single patient iPS cell line can cost up to one million dollars which isn’t feasible for the 1000’s of patients who need them. He admitted that the fate of personalized stem cell medicine, which once seemed so promising, now seems unrealistic because it’s time consuming and costly.

But with any obstacle, there is always a path around it. Under Yamanaka’s guidance, Japan is generating donor iPS cell lines that can be used to treat a large portion of the Japanese population. Yamanaka said that 100 lines would cover 100 million people in Japan and that 200 lines would be enough to cover the US population. iPS cell banks are being generated around the world, meaning that one day the millions of people suffering from the target diseases Yamanaka mentioned could be treated or even cured. Would this not fulfill a promise that was made about the potential of stem cell treatments?

Which brings me to my point, I don’t believe the promise of stem cells has been overstated. I think that it has yet to be realized, and it will take more research and more time to get there. As a community, we need to be understanding, patient, and supportive.

In my opinion (as a scientist aside from my role at CIRM), I believe that Yamanaka’s interview failed to reveal his optimism about the future of stem cell treatments. What I took from Yamanaka’s comments is that stem cell treatments can help a small number of patients with specific diseases right now. That’s not to say that stem cell research won’t produce promising treatments for other diseases in the future.

Retinal diseases and blood disorders are easier to target with stem cell treatments because only one type of cell needs to be replaced. It makes sense to tackle those diseases first and make sure that these stem cell treatments are effective and safe in patients before we focus on more complicated diseases where multiple cell types or organs are involved.

Part of the reason why scientists are unsure whether stem cell treatments can treat complex diseases is because we still don’t know the details of what causes these diseases. After we know more about what’s going wrong, including all the cell types and molecules involved, research might reveal new ways that stem cells could be used to help treat those diseases. Or on the other hand, stem cells could be used to model those diseases to help discover new drug treatments.

I’ve heard Yamanaka talk many times and recently I heard him speak at the World Alliance Forum in November, where he said that the two biggest hurdles we are facing for stem cell treatments to be successful is time and cost. After we overcome these hurdles, his outlook was optimistic that stem cell treatments could improve people’s lives. But he stressed that these advances will take time.

He shared a similar sentiment at the very end of the NY Times interview by referencing his father’s story and the decades it took to cure hepatitis C,

“You know, my father had a small factory. He injured his leg in the factory when I was in junior high. He had a transfusion, and he got hepatitis C. He passed away in 1989. Twenty-five years later, just two years ago, scientists developed a very effective cure. We now have a tablet. Three months and the virus is gone — it’s amazing. But it took 25 years. iPS cells are only 10 years old. The research takes time. That’s what everybody needs to understand.”

Yamanaka says more time is needed for stem cell treatments to become effective cures, but CIRM has already witnessed success. In our December Board meeting, we heard from two patients who were cured of genetic blood diseases by stem cell treatments that CIRM funded. One of them was diagnosed with severe combined immunodeficiency (SCID) and the other had chronic granulomatous disease (CGD). Both had their blood stem cells genetically engineered to removed disease-causing mutations and then transplanted back into their body to create a healthy immune system and cure them of their disease.

Hearing how grateful these patients and their families were to receive life-saving stem cell treatments and how this research brings new hope to other patients suffering from the same diseases, in my mind, fulfills the promise of stem cell research and makes funding stem cell treatments worth it.

I believe we will hear more and more of these success stories in the next decade and CIRM will most certainly play an important role in this future. There are others in the field who share a similar optimism for the future of stem cell treatments. Hank Greely, the Director for Law and the Biosciences at Stanford University, said in an interview with the Sacramento Bee about the future of CIRM,

Hank Greely, Stanford University

Hank Greely, Stanford University

“The next few years should determine just how good California’s investment has been. It is encouraging to see CIRM supporting so many clinical trials; it will be much more exciting when – and I do expect ‘when’ and not ‘if’ – one of those trials leads to an approved treatment.”

 


Related Links:

Stem cell stories that caught our eye: insights into stem cell biology through telomeres, reprogramming and lung disease

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.

Telomeres and stem cell stability: too much of a good thing

Just like those plastic tips at the end of shoelaces (fun fact: they’re called aglets), telomeres form a protective cap on the end of chromosomes. Because of the way DNA replication works, the telomeres shorten each time a cell divides. Trim away enough of the telomere over time and, like a frayed shoelace, the chromosomes become unstable and an easy target for damage which eventually leads to cell death.

telomere_caps

Telomeres (white dots) form a protective cap on chromsomes (gray). (Wikimedia) 

Stem cells are unique in that they contain an enzyme called telomerase that lengthens telomeres. Telomerase activity and telomere lengthening are critical for a stem cell’s ability to maintain virtually limitless cell divisions. So you’d assume the longer the telomere, the more stable the cell. But Salk Institute scientists reported this week that too much telomere can be just as bad, if not worse, than too little.

The CIRM-funded work, which was published in Nature Structural & Molecular Biology, used genetic engineering to artificially vary telomerase activity in human embryonic stem cells. Cells with low telomerase activity had shorter telomeres and died. This result wasn’t a surprise since the short telomeres-cell death observation has been well documented. Based on those results, the team was expecting cells with boosted telomerase activity and, in turn, extended telomeres would be especially stable. But that’s not what happened as senior author Jan Karlseder mentioned in a Salk press release:

“We were surprised to find that forcing cells to generate really long telomeres caused telomeric fragility, which can lead to initiation of cancer. These experiments question the generally accepted notion that artificially increasing telomeres could lengthen life or improve the health of an organism.”

The researchers also examined induced pluripotent stem (iPS) cells in the study and found that the cells contain “footprints” of telomere trimming. So the team is in a position to study how a cell’s telomere history relates to how well it can be reprogrammed into iPS cells. First author Teresa Rivera pointed out the big picture significance of this finding:

“Stem cell reprogramming is a major scientific breakthrough, but the methods are still being perfected. Understanding how telomere length is regulated is an important step toward realizing the promise of stem cell therapies and regenerative medicine.”

jan-karlseder_teresa-rivera-garcia0x8c7144w

Jan Karlseder and Teresa Rivera

Lego set of gene activators takes trial and error out of cellular reprogramming

To convert one cell type into another, stem cell researchers rely on educated guesses and a lot of trial and error. In fact, that’s how Shinya Yamanaka identified the four Yamanaka Factors which, when inserted into a skin cell, reprogram it into the embryonic stem cell-like state of an iPS cell. That ground-breaking discovery ten years ago has opened the way for researchers worldwide to specialize iPS cells into all sorts of cell types from nerve cells to liver cells. While some cell types are easy to generate this way, others are much more difficult.

Reporting this week in PNAS, a University of Wisconsin–Madison research team has developed a nifty systematic, high-throughput method for identifying the factors necessary to convert a cell from one type to another. Their strategy promises to free researchers from the costly and time consuming trial and error approach still in use today.

The centerpiece of their method is artificial transcription factors (ATFs). Now, natural transcription factors – Yamanaka’s Factors are examples – are proteins that bind DNA and activate or silence genes. Their impact on gene activity, in turn, can have a cascading effects on other genes and proteins ultimately causing, say a stem cell, to start making muscle proteins and turn into a muscle cell.

Transcription factors are very modular proteins – one part is responsible for binding DNA, another part for affecting gene activity and other parts that bind to other proteins. The ATFs generated in this study are like lego versions of natural transcription factors – each are constructed from combinations of different transcription factor parts. The team made nearly 3 million different ATFs.

As a proof of principle, the researchers tried reproducing Yamanaka’s original, groundbreaking iPS cell experiment. They inserted the ATFs into skin cells that already had 3 of the 4 Yamanaka factors, they left out Oct4. They successfully generated iPS with this approach and then went back and studied the makeup of the ATFs that had caused cells to reprogram into iPS cells. Senior author Aseem Ansari gave a great analogy in a university press release:

“Imagine you have millions of keys and only a unique key or combination of keys can turn a motor on. We test all those keys in parallel and when we see the motor fire up, we go back to see exactly which key switched it on.”

atf_ips_cells

Micrograph of induced pluripotent stem cells generated from artificial transcription factors. The cells express green fluorescent protein after a key gene known as Oct4 is activated. (ASUKA EGUCHI/UW-MADISON)

The analysis showed that these ATFs had stimulated gene activity cascades which didn’t directly involve Oct4 but yet ultimately activated it. This finding is important because it suggests that future cell conversion experiments could uncover some not so obvious cell fate pathways. Ansari explains this point further:

“It’s a way to induce cell fate conversions without having to know what genes might be important because we are able to test so many by using an unbiased library of molecules that can search nearly every corner of the genome.”

This sort of brute force method to accelerate research discoveries is music to our ears at CIRM because it ultimately could lead to therapies faster.

Search for clues to treat deadly lung disease

When researchers don’t understand what causes a particular disease, a typical strategy is to compare gene activity in diseased vs healthy cells and identify important differences. Those differences may lead to potential paths to developing a therapy. That’s the approach a collaborative team from Cincinnati Children’s Hospital and Cedars-Sinai Medical took to tackle idiopathic pulmonary fibrosis (IPF).

IPF is a chronic lung disease which causes scarring, or fibrosis, in the air sacs of the lung. This is the spot where oxygen is taken up by tiny blood vessels that surround the air sacs. With fibrosis, the air sacs stiffen and thicken and as a result less oxygen gets diffused into the blood and starves the body of oxygen.  IPF can lead to death within 2 to 5 years after diagnosis. Unfortunately, no cures exist and the cause is unknown, or idiopathic.

(Wikimedia)

(Wikimedia)

The transfer of oxygen from air sacs to blood vessels is an intricate one with many cell types involved. So pinpointing what goes wrong in IPF at a cellular and molecular level has proved difficult. In the current study, the scientists, for the first time, collected gene sequencing data from single cells from healthy and diseased lungs. This way, a precise cell by cell analysis of gene activity was possible.

One set of gene activity patterns found in healthy sample were connected to proper formation of a particular type of air sac cell called the aveolar type 2 lung cell. Other gene patterns were linked to abnormal IPF cell types. With this data in hand, the researchers can further investigate the role of these genes in IPF which may open up new therapy approaches to this deadly disease.

The study funded in part by CIRM was published this week in Journal of Clinical Investigation Insight and a press release about the study was picked up by PR Newswire.

How research on a rare disease turned into a faster way to make stem cells

Forest Gump. (Paramount Pictures)

Forest Gump. (Paramount Pictures)

If Forest Gump were a scientist, I’d like to think he would have said his iconic line a little differently. Dr. Gump would have said, “scientific research is like a box of chocolates – you never know what you’re gonna get.”

A new CIRM-funded study coming out of the Gladstone Institutes certainly proves this point. Published yesterday in the Proceedings of the National Academy of Sciences, the study found that a specific genetic mutation known to cause a rare disease called fibrodysplasia ossificans progressiva (FOP) makes it easier to reprogram adult skin cells into induced pluripotent stem cells (iPSCs).

Shinya Yamanaka received the Nobel Prize in medicine in 2012 for his seminal discovery of the iPSC technology, which enabled scientists to generate patient specific pluripotent stem cell lines from adult cells like skin and blood. These iPSC lines are useful for modeling disease in a dish, identifying new therapeutic drugs, and potentially for clinical applications in patients. However, one of the rate-limiting steps to this technology is the inefficient process of making iPSCs.

Yamanaka, a senior investigator at Gladstone, knows this problem all too well. In a Gladstone news release he commented, “inefficiency in creating iPSCs is a major roadblock toward applying this technology to biomedicine. Our study identified a surprising way to increase the number of iPSCs that we can generate.”

So how did Yamanaka and his colleagues discover this new trick for making iPSCs more efficiently? Originally, their intentions were to model a rare genetic disease called FOP. It’s commonly known as “stone man syndrome” because the disease converts normal muscle and connective tissue into bone either spontaneously or spurred by injury. Bone growth begins at a young age starting at the neck and progressively moving down the body. Because there is no treatment or cure, patients typically have a lifespan of only 40 years.

The Gladstone team wanted to understand this rare disease better by modeling it in a dish using iPSCs generated from patients with FOP. These patients had a genetic mutation in the ACVR1 gene, which plays an important role in the development of the embryo. FOP patients have a mutant form of ACVR1 that overstimulates this developmental pathway and boosts the activity of a protein called BMP (bone morphogenic protein). When BMP signaling is ramped up, they discovered that they could produce significantly more iPSCs from the skin cells of FOP patients compared to normal, healthy skin cells.

First author on the study, Yohei Hayashi, explained their hypothesis for why this mutation makes it easier to generate iPSCs:

“Originally, we wanted to establish a disease model for FOP that might help us understand how specific gene mutations affect bone formation. We were surprised to learn that cells from patients with FOP reprogrammed much more efficiently than cells from healthy patients. We think this may be because the same pathway that causes bone cells to proliferate also helps stem cells to regenerate.”

To be sure that enhanced BMP signaling caused by the ACVR1 mutation was the key to generating more iPSCs, they blocked this signal and discovered that much fewer iPSCs were made from FOP patient skin cells.

Senior Investigator Bruce Conklin, who was a co-author on this study, succinctly summarized the importance of their findings:

“This is the first reported case showing that a naturally occurring genetic mutation improves the efficiency of iPSC generation. Creating iPSCs from patient cells carrying genetic mutations is not only useful for disease modeling, but can also offer new insights into the reprogramming process.”

Gladstone investigators Bruce Conklin and Shinya Yamanaka. (Photo courtesy of Chris Goodfellow, Gladstone Institutes)

Gladstone investigators Bruce Conklin and Shinya Yamanaka. (Photo courtesy of Chris Goodfellow, Gladstone Institutes)

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

New Blog Series

257c3-shinya_yamanaka

Shinya Yamanaka

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

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

Here are the topics:

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

A Conference Dedicated to 10 Years of iPSCs

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

More details about the Symposium can be found here.

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

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

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

Stem cell stories that caught our eye: a surprising benefit of fasting, faster way to make iPSCs, unlocking the secret of leukemia cancer cells

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

Fasting

Is fasting the fountain of youth?

Among the many insults our bodies endure in old age is a weakened immune system which leaves the elderly more susceptible to infection. Chemotherapy patients also face the same predicament due to the immune suppressing effects of their toxic anticancer treatments. While many researchers aim to develop drugs or cell therapies to protect the immune system, a University of Southern California research report this week suggests an effective alternative intervention that’s startlingly straightforward: fasting for 72 hours.

The study published in Cell Stem Cell showed that cycles of prolonged fasting in older mice led to a decrease in white blood cells which in turn set off a regenerative burst of blood stem cells. This restart of the blood stem cells replenished the immune system with new white blood cells. In a pilot Phase 1 clinical trial, cancer patients who fasted 72 hours before receiving chemotherapy maintained normal levels of white blood cells.

A look at the molecular level of the process pointed to a decrease in the levels of a protein called PKA in stem cells during the fasting period. In a university press release carried by Science Daily, the study leader, Valter Longo, explained the significance of this finding:

“PKA is the key gene that needs to shut down in order for these stem cells to switch into regenerative mode. It gives the ‘okay’ for stem cells to go ahead and begin proliferating and rebuild the entire system. And the good news is that the body got rid of the parts of the system that might be damaged or old, the inefficient parts, during the fasting. Now, if you start with a system heavily damaged by chemotherapy or aging, fasting cycles can generate, literally, a new immune system.”

In additional to necessary follow up studies, the team is looking into whether fasting could benefit other organ systems besides the immune system. If the data holds up, it could be that regular fasting or direct targeting of PKA could put us on the road to a much more graceful and healthier aging process.

4955224186_31f969e6fd_m

Faster, cheaper, safer way to use iPS cells

Science, like traffic in any major city, never moves quite as quickly as you would like, but now Japanese researchers are teaming up to develop a faster, and cheaper way of using iPSC’s , pluripotent stem cells that are reprogrammed from adult cells, for transplants.

Part of the beauty of iPSCs is that because those cells came from the patient themselves, there is less risk of rejection. But there are problems with this method. Taking adult cells and turning them into enough cells to treat someone can take a long time. It’s expensive too.

But now researchers at Kyoto University and three other institutions in Japan have announced they are teaming up to change that. They want to create a stockpile of iPSCs that are resistant to immunological rejection, and are ready to be shipped out to researchers.

Having a stockpile of ready-to-use iPSCs on hand means researchers won’t have to wait months to develop their own, so they can speed up their work.

Shinya Yamanaka, who developed the technique to create iPSCs and won the Nobel prize for his efforts, say there’s another advantage with this collaboration. In a news article on Nikkei’s Asian Review he said these cells will have been screened to make sure they don’t carry any potentially cancer-causing mutations.

“We will take all possible measures to look into the safety in each case, and we’ll give the green light once we’ve determined they are sound scientifically. If there is any concern at all, we will put a stop to it.”

CIRM is already working towards a similar goal with our iPSC Initiative.

Unlocking the secrets of leukemia stem cells

the-walking-dead-season-6-zombies

Zombies: courtesy “The Walking Dead”

Any article that has an opening sentence that says “Cancer stem cells are like zombies” has to be worth reading. And a report in ScienceMag  that explains how pre-leukemia white blood cell precursors become leukemia cancer stem cells is definitely worth reading.

The article is about a study in the journal Cell Stem Cell by researchers at UC San Diego. The senior author is Catriona Jamieson:

“In this study, we showed that cancer stem cells co-opt an RNA editing system to clone themselves. What’s more, we found a method to dial it down.”

An enzyme called ADAR1 is known to spur cancer growth by manipulating small pieces of genetic material known as microRNA. Jamieson and her team wanted to track how that was done. They discovered it is a cascade of events, and that once the first step is taken a series of others quickly followed on.

They found that when white blood cells have a genetic mutation that is linked to leukemia, they are prone to inflammation. That inflammation then activates ADAR1, which in turn slows down a segment of microRNA called let-7 resulting in increased cell growth. The end result is that the white blood cells that began this cascade become leukemia stem cells and spread an aggressive and frequently treatment-resistant form of the blood cancer.

Having uncovered how ADAR1 works Jamieson and her team then tried to find a way to stop it. They discovered that by blocking the white blood cells susceptibility to inflammation, they could prevent the cascade from even starting. They also found that by using a compound called 8-Aza they could impede ADAR1’s ability to stimulate cell growth by around 40 percent.

Jamieson

Catriona Jamieson – definitely not a zombie

Jamieson says the findings open up all sorts of possibilities:

“Based on this research, we believe that detecting ADAR1 activity will be important for predicting cancer progression. In addition, inhibiting this enzyme represents a unique therapeutic vulnerability in cancer stem cells with active inflammatory signaling that may respond to pharmacologic inhibitors of inflammation sensitivity or selective ADAR1 inhibitors that are currently being developed.”

This wasn’t a CIRM-funded study but we have supported other projects by Dr. Jamieson that have led to clinical trials.

 

 

 

 

New study says stem cells derived from older people may have more problems than we thought.

heart muscle from iPS

iPS-generated heart muscle cells

Ever since 2006 when Japanese researcher Shinya Yamanaka showed that you could take an adult cell, such as those in your skin, and reprogram it to act like an embryonic stem cell, the scientific world has looked at these induced pluripotent stem (iPS) cells as a potential game changer. They had the ability to convert a person’s own cells into any other kind of cell in the body, potentially offering a way of creating personalized treatments for a wide variety of diseases.

Fears that this reprogramming method might create some cancer-causing genetic mutations seemed to have been eased when two recent studies suggested this approach is relatively safe and unlikely to lead to any tumors in patients. We funded one of those studies and blogged about it.

Reason for caution

But now a new study in the journal Cell Stem Cell  says “not so fast”. The study says the older the person is, the greater the chance that any iPS cells derived from their tissue could contain potentially harmful mutations, but not in the places you would normally think.

A team at Oregon Health and Science University, led by renowned scientist Shoukhrat Mitalipov, took skin and blood samples from a 72-year-old man. The scientists examined the DNA from those samples, then reprogrammed those cells into iPS cells, and examined the DNA from the new stem cells.

Mitalipov-2

Shoukhrat Mitalipov: photo courtesy Oregon Health and Science University

When they looked at the cells collectively the levels of mutations in the new iPS cells appeared to be quite low. But when they looked at individual cells, they noticed a wide variety of mutations in the mitochondria in those cells.

Now, mitochondria play an important role in the life of a cell. They act as a kind of battery, providing the power a cell needs to perform a variety of functions such as signaling and cell growth. But while they are part of the cell, mitochondria have their own genomes. It was here that the researchers found the mutations that raised questions.

Older cells have more problems

Next they repeated the experiment but this time took skin and blood samples from 14 people between the ages of 24 and 72. They found that  older people had more genetic mutations in their mitochondrial DNA that were then transferred to the iPS cells derived from those people. In some cases up to 80 percent of the iPS cell lines generated showed mitochondrial mutations. That’s really important because the greater the amount of mutated mitochondrial DNA in a cell, the more its ability to function is compromised.

In a news release, Mitalipov says this should cause people to pause before using iPS cells derived from an older person for therapeutic purposes:

“Pathogenic mutations in our mitochondrial DNA have long been thought to be a driving force in aging and age-related diseases, though clear evidence was missing. Now with that evidence at hand, we know that we must screen stem cells for mutations or collect them at younger age to ensure their mitochondrial genes are healthy. This foundational knowledge of how cells are damaged in the natural process of aging may help to illuminate the role of mutated mitochondria in degenerative disease.”

To be clear, the researchers are not saying these iPS cells from older people should never be used, only that they need to be carefully screened to ensure they are not seriously damaged before being transplanted into a patient.

A possible solution

Mitalipov suggests a simple way around the problem would be to identify the iPS cell with the best mitochondria, and then use that as the basis for a new cell line that could then be used to create a new therapy.

Taosheng Huang, a researcher at the Mitochondrial Disorders Program at Cincinnati Children’s Hospital Medical Center, is quoted in the news release saying the lesson is clear:

“If you want to use iPS cells in a human, you must check for mutations in the mitochondrial genome. Every single cell can be different. Two cells next to each other could have different mutations or different percentages of mutations.”

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”.

 

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.


 

Related Links:

More than Meets the Eye: Stem Cells Generated using Different Methods Produce Different Types of Cells

What’s the best way to make a fully versatile, ‘pluripotent,’ stem cell? Three different methods each have their pluses and minuses. But now new research has found that the stem cells created by each method, while similar on the surface, show vast differences.

The findings, published online today in the journal Nature, reveal new insights into stem cells’ underlying cellular machinery—which is of utmost importance as researchers transform their discoveries from the lab and into much-needed therapies for patients.

Scanning electron micrograph of cultured human neuron from induced pluripotent stem cell.  [Credit: Mark Ellisman and Thomas Deerinck, National Center for Microscopy and Imaging Research, UC San Diego]

Scanning electron micrograph of cultured human neuron from induced pluripotent stem cell. [Credit: Mark Ellisman and Thomas Deerinck, National Center for Microscopy and Imaging Research, UC San Diego]

Stem cells have held promise for regenerating tissues, or even organs, lost or damaged by injury or disease. This is due to stem cells’ ‘pluripotency’—their ability to transform into virtually any cell in the body. Initially, scientists used stem cells extracted from unused embryos that consenting couples had donated to research. But the use of these so-called embryonic stem cells, or ES cells, has since been limited due to ethical considerations and early limits to federal funding.

So scientists have been on the hunt for an alternative method of creating pluripotent cells. And so far, they have come up with two.

One, called somatic cell nuclear transfer (SCNT) takes the genetic material of an adult cell and transplants it into an unfertilized egg. The second method transforms adult cells, such as skin or blood, back into embryonic-like stem cells—called induced pluripotent stem cells, or iPS cells—by manipulating various genes.

Each of the newer methods has its pluses and minuses—but which produces cells that most closely resemble ES cells, still considered the “Gold Standard” in stem cell biology? Since the success of the SCNT technique is so recent, no one had taken a close look until now. So a collaboration of researchers from the University of California, San Diego (UCSD), The Salk Institute for Biological Sciences and Oregon Health & Science University (OHSU), compared the two methods side by side. And what they found was surprising.

Dr. Louise Laurent, co-senior author from UCSD, explained in today’s news release:

“The nuclear transfer ES cells are much more similar to real ES cells than the iPS cells. They are more completely reprogrammed and have fewer alterations in gene expression and DNA methylation levels that are attributable to the reprogramming process itself.”

iPS cell technology, which was pioneered in 2006 by Shinya Yamanaka, offers a series of advantages over traditional ES cells. As Laurent continued:

“The ability to make personalized iPS cells from a patient that could be transplanted back into that patient has generated excitement because it would eliminate the need for immunosuppression.”

iPS cells have generated so much excitement, in fact, that Yamanaka was awarded the 2012 Nobel Prize in Physiology or Medicine for developing this technique.

The SCNT method was developed more recently by OHSU’s Dr. Shoukhrat Mitalipov. The current researchers generated lines of cells using both methods. After confirming that each line was, in fact, pluripotent, they used advanced genomics techniques to examine the biochemical process called ‘DNA methylation’ in each line.

DNA methylation is a fundamental chemical process within each cell. It’s responsible for switching key genes on and off at precise intervals. In recent years, researchers have discovered that the order and timing of this process is vital for the correct development of the cell. As Dr. Joseph Ecker, co-senior author from the Salk Institute, explained:

“If you believe that gene expression and DNA methylation are important, which we do, the closer you get to the patterns of embryonic cells, the better. Right now, nuclear transfer cells look closer to the embryonic stem cells than do the iPS cells.”

However, while the scientists confirmed that SCNT cells more closely resemble ES cells, the process of producing them is far from ideal. First, the SCNT method is technically difficult. And second, federal funds still cannot be used in this procedure—representing a significant hurdle to being widely adopted.

On the other hand, iPS cell generation is, by comparison, a much easier process technically. So perhaps these findings can spur the development of an improved method, taking the technological ease of iPS cell generation and marrying it with the accuracy of the SCNT method. Laurent argues that this could yield a new and improved approach:

“Our results have shown that widely used iPS cell reprogramming methods make cells that are similar to standard ES cells in broad strokes, but there are important differences when you look really closely. By using the egg cell to do the job, we can get much closer to the real thing. If we can figure out what factors in the egg drive the reprogramming process, maybe we can design a better iPS cell reprogramming method.”