UCLA scientists begin a journey to restore the sense of touch in paralyzed patients

Yesterday, CIRM-funded scientists at UCLA published an interesting study that sheds light on the development of sensory neurons, a type of nerve cell that is damaged in patients with spinal cord injury. Their early-stage findings could potentially, down the road, lead to the development of stem cell-based treatments that rebuild the sensory nervous system in paralyzed people that have lost their sense of touch.

Dr. Samantha Butler, a CIRM grantee and professor at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, led the study, which was published in the journal eLife.

Restoring sensation

Butler and her team were interested in understanding the basic development of sensory interneurons in the spinal cord. These are nerve cells in the spinal cord that receive sensory signals from the environment outside the body (like heat, pain and touch) and relay these signals to the brain where the senses are then perceived.

Developing spinal cord injury treatments often focus on the loss of movement caused by damage to the motor neurons in the spine that control our muscles. However, the damage caused to sensory neurons in the spine can be just as debilitating to people with paralysis. Without being able to feel whether a surface is hot or cold, paralyzed patients can sustain serious burn injuries.

Butler commented in a UCLA news release that attempting to restoring sensation in paralyzed patients is just as important as restoring movement:

Samantha Butler

“The understanding of sensory interneuron development has lagged far behind that of another class of neurons—called motor neurons—which control the body’s ability to move. This lack in understanding belies the importance of sensation: it is at the core of human experience. Some patients faced with the reality of paralysis place the recovery of the sense of touch above movement.”

BMPs are important for sensory neuron development

To restore sensation in paralyzed patients, scientists need to replace the sensory neurons that are damaged in the spine. To create these neurons, Butler looked to proteins involved in the early development of the spinal cord called bone morphogenetic proteins or BMPs.

BMPs are an important family of signaling proteins that influence development of the embryo. Their signaling can determine the fate or identity of cells including cells that make up the developing spinal cord.

It was previously thought that the concentration of BMPs determined what type of sensory neuron a stem cell would develop into, but Butler’s team found the opposite in their research. By studying developing chick embryos, they discovered that the type, not the concentration, of BMP matters when determining what subtype of sensory neuron is produced. Increasing the amount of a particular BMP in the chick spinal cord only produced more of the same type of sensory interneuron rather than creating a different type.

Increasing the concentration of a certain type of BMP increases the production of the same categories of sensory interneurons (red and green). (Image credit: UCLA)

The scientists confirmed these findings using mouse embryonic stem cells grown in the lab. Interestingly a different set of BMPs were responsible for deciding sensory neuron fate in the mouse stem cell model compared to the chick embryo. But the finding that different BMPs determine sensory neuron identity was consistent.

So what and what’s next?

While this research is still in its early stages, the findings are important because they offer a better understanding of sensory neuron development in the spinal cord. This research also hints at the potential for stem cell-based therapies that replace or restore the function of sensory neurons in paralyzed patients.

Madeline Andrews, the first author of the study, concluded:

“Central nervous system injuries and diseases are particularly devastating because the brain and spinal cord are unable to regenerate. Replacing damaged tissue with sensory interneurons derived from stem cells is a promising therapeutic strategy. Our research, which provides key insights into how sensory interneurons naturally develop, gets us one step closer to that goal.”

The next stop on the team’s research journey is to understand how BMPs influence sensory neuron development in a human stem cell model. The UCLA news release gave a sneak preview of their plans in the coming years.

“Butler’s team now plans to apply their findings to human stem cells as well as drug testing platforms that target diseased sensory interneurons. They also hope to investigate the feasibility of using sensory interneurons in cellular replacement therapies that may one day restore sensation to paralyzed patients.”

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A trip to the OR started CIRM’s latest Board member on a career in science

The CIRM Board is pretty big, 29 members, all of whom have very different backgrounds and experiences. That’s one of its strengths, the diversity of members and the sheer range of expertise they bring to this work.

David Martin

Our newest member, Dr. David Martin, is the Chair and CEO of AvidBiotics Corp., a biotech company in South San Francisco. He has a very impressive resume including leadership roles at Genentech, DuPont Merck and Chiron. You can read more about that in our news release.

But we wanted to go beyond the obvious reasons why he was appointed by California State Treasurer John Chiang (who celebrated Dr. Martin’s “very distinguished career in both academics and the biotech industry”) and find a little bit more about him as a person.

We began by asking him how he got interested in science:

“When I was in junior high school, my father, a pediatrician, managed for me to witness at close-hand several surgical procedures in the O.R. When I was in high school my biology teachers were disasters, but I really enjoyed math and physics so I went to an engineering school.  After a year I rejected carrying a 14-inch slide rule on my belt like the other geeks and switched my major to biology. The biology lab excited me, and I changed my courses to prepare for medical school.  There I took off a year for a research training program and a real research lab experience.  I was hooked.”

What have been some of the biggest influences in your career?

Jim Wyngaarden’s research training program (supported by the National Science Foundation – as a precursor to the National Institute of Health’s  Medical Scientist Training Program) and working in Jim’s lab at Duke.  I then had nearly a decade of direct exposure to Gordon Tomkins, first when I was as a post-doc at NIH and then as a faculty member at UCSF.  Third was my many years exposure to Bob Swanson at Genentech.  Each was a remarkable and quite unique mentor.”

You have been a part of some of the biggest players in drug research and development – Genentech, DuPont Merck, Chiron – what are the biggest advances you have seen over the years?

“The discovery, early development, and nearly explosive expansion of recombinant DNA technologies and of their broad applications in the life sciences. Today one can already see on the near horizon a similar, very rapid expansion of stem cell applications to regenerative medicine, and it will not be limited to regenerative medicine.”

Dr. Martin says he feels privileged and enthused to be joining the CIRM Board and hopes his experience will be valuable to the agency:

“Fortuitously, I’ve been in the right place at the right time more than once as a physician-scientist—in both academe and industry; hopefully those experiences and perspectives may be of benefit to CIRM.”

Like many people fortunate enough to live in the San Francisco Bay Area he likes to get out of the lab/office as much as possible to enjoy all that the region has to offer:

“I enjoy bicycling, hiking and fly fishing—when I can find the time.”

We are delighted to welcome Dr. Martin to the CIRM team.

Blocking spike in stem cell growth after brain injury may lessen memory decline, seizures

Survivors of traumatic brain injury (TBI) often suffer from debilitating, life changing symptoms like memory decline and epileptic seizures. Researchers had observed that following TBI, a stem cell-rich area of the brain provides a spike in new nerve cell growth, presumably to help replace damaged or destroyed brain cells. But, like a lot of things in biology, more is not always better. And a new report in Stem Cell Reports provides evidence that this spark of brain cell growth shortly after TBI may actually be responsible for post-injury seizures as well as long-term memory problems for people with this condition.The Rutgers University research team behind the study came to this counterintuitive conclusion by examining brain injury in laboratory rats. They showed that brain cells at the injury site that are known to play a role in memory had doubled in number within three days after injury. But a month later, these brain cells had decreased by more than half the amount seen in rats without injury. Neural stem cells, which develop into the mature cells found in the brain, showed this same up and down pattern, suggesting they were responsible for the loss of the brain cells. Lead scientist, professor Viji Santhakumar, described how these changes in brain cell growth lead to brain injury symptoms:

“There is an initial increase in birth of new neurons after a brain injury but within weeks, there is a dramatic decrease in the normal rate at which neurons are born, depleting brain cells that under normal circumstances should be there to replace damaged cells and repair the brain’s network,” she said in a press release. “The excess new neurons lead to epileptic seizures and could contribute to cognitive decline. It is normal for the birth of new neurons to decline as we age. But what we found in our study was that after a head injury the decline seems to be more rapid.”

The researchers next aimed to slow down this increase in nerve cell growth after injury. To accomplish this goal, they used an anti-cancer drug currently in clinical trials which has been known to block the growth and survival of new nerve cells. Sure enough, the drug blocked this initial, rapid burst in nerve cells in the rats, which prevented the long-term decline in the brain cells that are involved in memory decline. The team also reported that the rats were less vulnerable to seizures when this drug was administered.

“That’s why we believe that limiting this process might be beneficial to stopping seizures after brain injury,” Dr. Santhakumar commented.

Hopefully, these findings will one day help lessen these short- and long-term, life-altering symptoms seen after brain injury.

Stem Cell Stories That Caught our Eye: Insights into a healthy brain, targeting mutant cancers and commercializing cell therapies

Here’s your weekly roundup of interesting stem cell stories!

Partnership for a healthy brain. To differentiate or not to differentiate. That is the question the stem cells in our tissues and organs face.

In the case of the brain, neural precursor cells can either remain in a stem cell state or they can differentiate into mature brain cells called neurons and astrocytes. Scientists are interested in understanding how the brain maintains the balance between these different cell states in order to understand how disruption to this balance are associated with psychiatric and neurodegenerative diseases.

Scientists from the Salk Institute, led by Genetics Professor Rusty Gage, published a study this week in Cell Stem Cell that sheds light on how this imbalance can cause brain disease. They found that a partnership between two proteins determines whether a neural precursor develops into a neuron or an astrocyte.

One of these proteins is called Nup153. It’s a protein that’s part of the nuclear pore complex, which sits on the surface of the nuclear membrane and controls the entry and exit of various proteins and molecules. In collaboration with another Salk team under the leadership of Martin Hetzer, Gage discovered that Nup153 was expressed at different levels depending on the cell type. Neural precursors had high levels of Nup153 protein, immature neurons had what they defined as an intermediate level while astrocytes had the lowest level.

When they blocked the function of Nup153, neural precursors differentiated, which led them to conclude that the levels of Nup153 can influence the fate of neural precursor cells. The teams also discovered that Nup153 interacts with the transcription factor Sox2 and that the levels of Sox2 in the different cell types was similar to the levels of Nup153.

A fluorescent microscopy image shows Nup153 (red) in pore complexes encircling and associating with Sox2 (green) in a precursor cell nucleus. Credit: Salk Institute/Waitt Center

In a Salk News release, first author on the study, Tomohisa Toda, explained how their findings shed light on basic cellular processes:

“The fact that we were able to connect transcription factors, which are mobile switches, to the pore complex, which is a very stable structure, offers a clue as to how cells maintain their identity through regulated gene expression.”

Gage’s team will next study how this partnership between the nuclear pore complex and transcription factors can influence the function of neurons in hopes of gaining more understanding of how an imbalance in these interactions can lead to neurological diseases.

“Increasingly, we are learning that diseases like schizophrenia, depression and Alzheimer’s all have a cellular basis. So we are eager to understand how specific brain cells develop, what keeps them healthy and why advancing age or other factors can lead to disease.”

Tomohisa Toda and Rusty Gage. Credit: Salk Institute

Targeting KRAS Mutant Cancer.

CIRM-funded scientists at UC San Diego School of Medicine have developed a new strategy to target cancers that are caused by a mutation in the KRAS gene. Their findings were published in the journal Cancer Discovery.

The KRAS protein is essential for normal signaling processes in tissues, but mutant versions of this protein can cause cancer. According to a UC San Diego Health news release about the study, “there are currently no effective treatments for the 95 percent of pancreatic cancers and up to 30 percent of non-small cell lung cancers with KRAS mutations.”

To address this need, the team identified a biomarker called αvb3 that is associated with cancers dependent on the KRAS mutation. They observed that a protein called Galectin-3 binds to αvb3, which is an integrin receptor on the surface of cancer cells, to promote mutant KRAS’s cancer-causing ability.

This realization offered the team a path towards potential treatments. By inhibiting Galectin-3 with a drug called GCS-100, the scientists would make KRAS-addicted cancers go cold turkey. Senior author on the study, David Cheresh, explained,

“This may be among the first approaches to successfully target KRAS mutant cancers. Previously, we didn’t understand why only certain KRAS-initiated cancers would remain addicted to the mutation. Now we understand that expression of integrin αvb3 creates the addiction to KRAS. And it’s those addicted cancers that we feel will be most susceptible to targeting this pathway using Galectin-3 inhibitors.”

Cheresh concluded that this novel approach could pave the way for a personalized medicine approach for KRAS-addicted cancers.

“KRAS mutations impact a large number of patients with cancer. If a patient has a KRAS mutant cancer, and the cancer is also positive for αvb3, then the patient could be a candidate for a therapeutic that targets this pathway. Our work suggests a personalized medicine approach to identify and exploit KRAS addicted tumors, providing a new opportunity to halt the progression of tumors that currently have no viable targeted therapeutic options.”

Commercializing cell therapy.

Our friends at RegMedNet made an infographic that illustrates how cell therapies have developed over time and how these therapies are advancing towards commercialization.

The infographic states, “The cell therapy industry is rapidly evolving, with new techniques, technology and applications being developed all the time. After some high-profile failures, all eyes are on regulating existing therapies to ensure patient safety is paramount. Legislators, regulators and other stakeholders around the world are navigating a difficult line between hope, hype and the scientific evidence.”

Check out their timeline below and visit the RegMedNet website for more news and information about the regenerative medicine field.

Attractive new regenerative medicine tool uses magnets to shape and stimulate stem cells

The ultimate goal of tissue engineers who work in the regenerative medicine field is to replace damaged or diseased organs with new ones built from stem cells. To accomplish the feat, these researchers are developing new tools and techniques to manipulate and specialize stem cells into three dimensional structures. Some popular methods – which we’ve blogged about often – include the use of bioscaffolds as well as 3D bioprinting . This week, a research team at the Laboratoire Matière et Systèmes Complexes in France has developed an attractive (pun intended!) new tool that uses magnetized stem cells to both manipulate and stimulate the cells into 3D shapes.

The magnetic stretcher: this all-in-one system can both form and mechanically stimulate an aggregate of magnetized embryonic stem cells. Image: © Claire Wilhelm / Laboratoire Matière et systèmes complexes (CNRS/Université Paris Diderot).

The study, reported on Monday in Nature Communications, used embryonic stem cells which were incubated with magnetic nanoparticles. The cells readily take up the nanoparticles which allowed the scientists to group the individual cells using magnets. But first the team needed to show that the nanoparticles had no negative effects on the cells. Comparing the iron nanoparticle-laden stem cells to iron-free cells showed no difference in the cells’ survival and their ability to divide.

It was also important to make sure the introduction of nanoparticles had no impact on the stem cell’s pluripotency; that is, its ability to maintain its unspecialized state. A visual check of the cells through a microscope showed that they grew together in rounded clumps, a hallmark of undifferentiated, pluripotent cells. In addition, the key genes that bestow pluripotency onto embryonic stem cells were still active after the addition of the nanoparticles.

The stem cells’ ability to mature into various cell types, like heart muscle or nerve, is key to any successful tissue engineering project. So, the next important assessment of these magnetized cells was to make sure their ability to differentiate, or specialize, was still intact. The typical first step to differentiating embryonic stem cells is to form so-called embryoid bodies (EBs), which are 3D groups of pluripotent stem cells which begin differentiating into the three fundamental tissues types: mesoderm (gives rise to muscle, bone, fat), ectoderm (gives rise to nerve, hair, eyes), endoderm (gives rise to intestines, liver). Using a popular technique, called the hanging drop method, the team showed that the presence of the nanoparticles did not negatively affect embryoid body formation.

In fact, the use of magnets to form embryoid bodies provided several advantages over the hanging drop method. The hanging drop technique requires multiple, time-consuming steps and the resulting embryoid bodies tend to be inconsistent in size and shape. Use of the magnets, on the other hand, instantaneously assembled the stem cells into consistently round aggregates. And by precisely adjusting the magnetic force used, the scientists could also vary the size of the embyroid body, which is an important variable to control since the embryoid size can impact its ability to differentiate.

While the magnet used to form the embryoid bodies was kept stable, the researchers included another magnet which they could move. With this setup, the team was able to stretch and shape the group of cells without the need of scaffolds or the need to physically contact the cells. Several previous studies, using flat, 2-dimensional petri dishes, have shown that the stiffness and flexibility of the dish can stimulate gene activity by affecting cell shape. In this study, the researchers found that when the magnet was moved in a cyclical pattern that imitates the rhythm of a heart beat, the embryoid bodies were, if you can believe it, nudged toward a heart muscle fate. A press release by France’s National Center of Scientific Research (CNRS), which funded the study, explained the big picture implications of this new technique:

“This “all-in-one” approach, which makes it possible to build and manipulate tissue within the same system, could thus prove to be a powerful tool both for biophysical studies and tissue engineering.”

Protein that turns normal cells into cancer stem cells offers target to fight colon cancer

colon-cancer

Colon cancer: Photo courtesy WebMD

Colon cancer is a global killer. Each year more than one million people worldwide are diagnosed with it; more than half a million die from it. If diagnosed early enough the standard treatment involves surgery, chemotherapy, radiation or targeted drug therapy to destroy the tumors. In many cases this may work. But in some cases, while this approach helps put people in remission, eventually the cancer returns, spreads throughout the body, and ultimately proves fatal.

Now researchers may have identified a protein that causes normal cells to become cancerous, and turn into cancer stem cells (CSCs). This discovery could help provide a new target for anti-cancer therapies.

Cancer stem cells are devilishly tricky. While most cancer cells are killed by chemotherapy or other therapies, cancer stem cells are able to lie dormant and hide, then emerge later to grow and spread, causing the person to relapse and the cancer to return.

In a study published in Nature Research’s Scientific Reports, researchers at SU Health New Orleans School of Medicine and Stanley S. Scott Cancer Center identified a protein, called SATB2, that appears to act as an “on/off” switch for specific genes inside a cancer cell.

In normal, healthy colorectal tissue SATB2 is not active, but in colorectal cancer it is highly active, found in around 85 percent of tumors. So, working with mice, the researchers inserted extra copies of the SATB2 gene, which produced more SATB2 protein in normal colorectal tissue. They found that this produced profound changes in the cell, leading to uncontrolled cell growth. In effect it turned a normal cell into a cancer stem cell.

As the researchers state in their paper:

“These data suggest that SATB2 can transform normal colon epithelial cells to CSCs/progenitor-like cells which play significant roles in cancer initiation, promotion and metastasis.”

When the researchers took colorectal cancer cells and inhibited SATB2 they found that this not only suppressed the growth of the cancer and it’s ability to spread, it also prevented those cancer cells from becoming cancer stem cells.

In a news release about the study Dr. Rakesh Srivastava,  the senior author on the paper, said the findings are important:

“Since the SATB2 protein is highly expressed in the colorectal cell lines and tissues, it can be an attractive target for therapy, diagnosis and prognosis.”

Because SATB2 is found in other cancers too, such as breast cancer, these findings may hold significance for more than just colorectal cancer.

The next step is to repeat the study in mice that have been genetically modified to better reflect the way colon cancer shows up in people. The team hope this will not only confirm their findings, but also give them a deeper understanding of the role that SATB2 plays in cancer formation and spread.

CIRM-funded scientists discover a new way to make stem cells using antibodies

Just as learning a new skill takes time to hone, scientific discoveries take time to perfect. Such is the case with induced pluripotent stem cells (iPSCs), the Nobel Prize winning technology that reprograms mature adult cells back into a pluripotent stem cell state. iPSCs are a powerful tool because they can develop into any cell found in the body. Scientists use iPSCs to model diseases in a dish, screen for new drugs, and to develop stem cell-based therapies for patients.

iPSCs grown in a cell culture dish.

The original iPSC technology, discovered by Dr. Shinya Yamanaka in 2006, requires viral delivery of four transcription factor genes, Oct4, Sox2, Klf4, and c-Myc, into the nucleus of an adult cell. These genes are inserted into the genome where they are activated to churn out their respective proteins. The combined expression of these four factors (OSKM) turns off the genetic programming of an adult cell and turns on the programming for a pluripotent stem cell.

The technology is pretty neat and allows scientists to make iPSCs from patients using a variety of different tissue sources including skin, blood, and even urine. However, there is a catch. Inserting reprogramming genes into a cell’s genome can be disruptive if the reprogramming genes fail to switch off or can cause cancer if nefarious oncogenes are turned on.

In response to this concern, scientists are developing alternative methods for making iPSCs using non-invasive methods. A CIRM-funded team from The Scripps Research Institute (TSRI) published such a study yesterday in the journal Nature Biotechnology.

Led by senior author and CIRM grantee Dr. Kristin Baldwin, the TSRI team screened a large library of antibodies – proteins that recognize and bind to specific molecules – to identify ones that could substitute for the OSKM reprogramming factors. The hope was that some of these antibodies would bind to proteins on the surface of cells and turn on a molecular signaling cascade from the outside that would turn on the appropriate reprogramming genes from the inside of the cell.

The scientists screened over 100 million antibodies and found ones that could replace three of the four reprogramming factors (Oct4, Sox2, and c-Myc) when reprogramming mouse skin cells into iPSCs. They were unable to find an antibody to replace Klf4 in the current study but have it on their to-do list for future studies.

Dr. Baldwin explained how her team’s findings improve upon previous reprogramming methods in a TSRI news release,

Kristen Baldwin

“This result suggests that ultimately we might be able to make IPSCs without putting anything in the cell nucleus, which potentially means that these stem cells will have fewer mutations and overall better properties.”

 

Other groups have published other non-invasive iPSC reprogramming methods using cocktails of chemicals, proteins or microRNAs in place of virally delivering genes to make iPSCs. However, Baldwin’s study is the first (to our knowledge) to use antibodies to achieve this feat.

An added benefit to antibody reprogramming is that the team was able to learn more about the signaling pathways that were naturally activated by the iPSC reprogramming antibodies.

“The scientists found that one of the Sox2-replacing antibodies binds to a protein on the cell membrane called Basp1. This binding event blocks Basp1’s normal activity and thus removes the restraints on WT1, a transcription factor protein that works in the cell nucleus. WT1, unleashed, then alters the activity of multiple genes, ultimately including Sox2’s, to promote the stem cell state using a different order of events than when using the original reprogramming factors.”

iPSCs made by antibody reprogramming could address some of the long-standing issues associated with more traditional reprogramming methods and could offer further insights into the complex signaling required to turn adult cells back into a pluripotent state. Baldwin and her team are now on the hunt for antibodies that will reprogram human (rather than mouse) cells into iPSCs. Stay tuned!

UCLA launches CIRM-funded clinical trial using engineered blood stem cells to treat skin cancer

It’s not uncommon for biomedical institutes as well as their funding partners to announce through press releases that a clinical trial they’re running has gotten off the ground and has started to enroll patients. For an outsider looking in, it may seem like they’re jumping the gun a bit. No patients have received the therapy. No cures have been declared. So why all the hubbub at the start?

The reality is this: the launch of a clinical trial isn’t a beginning. It represents many years of effort by many researchers and a lot of funding to take an idea and develop it into a tangible product that has been given clearance to be tested in people to potentially save their lives. That’s why this important milestone deserves to be recognized. So, we were excited to get the word out, in the form of a press release , that UCLA had announced this morning the launch of a CIRM-funded clinical trial testing a therapy for hard-to-treat cancers.

The UCLA clinical trial genetically alters a patient’s hematopoietic stem cells give rise to T cells that are efficient cancer killers.

It’s estimated that metastasis, or the spread of cancer to other parts of the body, is responsible for 90% of cancer deaths. Though radiation and chemotherapy treatments can stop a tumor in its tracks, a small population of cancer stem cells in the tumor lie dormant and can evade those anti-cancer approaches. Because of their unlimited potential to divide, the cancer stem cells regrow the tumor leading to its inevitable return and spread. Oncologists clearly need new approaches to help patients with this unmet medical need.

That’s where today’s clinical trial launch comes into the picture. Dr. Antonio Ribas, a member of the UCLA Broad Stem Cell Research Center, and his team have genetically engineered cancer-killing white blood cells called T cells and blood-forming stem cells collected from patients to produce a protein that, like a key in a lock, recognizes a protein found almost exclusively on the surface of many types of cancer. When the T cells are transfused back into the patient, they can more efficiently track down and eradicate hard-to-treat skin cancer stem cells. At the same, the transfused blood stem cells – which specialize into all the various immune system cells – provide a long-term supply of T cells for continued protection against reoccurrence of the tumor.

“Few options exist for the treatment of patients whose cancers have metastasized due to resistance to current therapies,” Ribas said in the UCLA press release. “This clinical trial will allow us to try a new approach that engineers the body’s immune system to fight metastasized tumors similar to how it fights germs and viruses.”

 

And as Dr. Maria Millan, CIRM’s President & CEO (interim), described in our accompanying press release, CIRM will be an ever-present partner to help Ribas’ team get the clinical trial smoothly out of the starting gate and provide the support needed to carry the therapy to its completion:

“This trial is the first step in developing a therapy that could alleviate the complications resulting from cancer metastases as well as potentially improving outcomes in cancer patients where there are currently no effective treatment options. We are confident that CIRM’s funding and partnership, in combination with the expertise provided by our Alpha Stem Cell Clinic network, will give provide critical support for the successful conduct of this important clinical trial.”

 

To learn more about this clinical trial, visit its page at clinicaltrials.gov. If you think you might be eligible to enroll, please contact Clinical Research Coordinator Justin Tran by email at justintran@mednet.ucla.edu or by phone at 310-206-2090.

Stem Cell Stories That Caught our Eye: Duchenne muscular dystrophy and short telomeres, motor neurons from skin, and students today, stem cell scientists tomorrow

Short telomeres associated with Duchenne Muscular Dystrophy.

Duchenne Muscular Dystrophy (DMD) is a severe muscle wasting disease that typically affects young men. There is no cure for DMD and the average life expectancy is 26. These are troubling facts that scientists at the University of Pennsylvania are hoping to change with their recent findings in Stem Cell Reports.

Muscle stem cells with telomeres shown in red. (Credit: Penn Medicine)

The team discovered that the muscle stem cells in DMD patients have shortened telomeres, which are the protective caps on the ends of chromosomes that prevent the loss of precious genetic information during cell division. Each time a cell divides, a small section of telomere is lost. This typically isn’t a problem because telomeres are long enough to protect cells through many divisions.

But it turns out this is not the case for the telomeres in the muscle stem cells of DMD patients. Because DMD patients have weak muscles, they experience constant muscle damage and their muscle stem cells have to divide more frequently (basically non-stop) to repair and replace muscle tissue. This is bad news for the telomeres in their muscle stem cells. Foteini Mourkioti, senior author on the study, explained in a news release,

“We found that in boys with DMD, the telomeres are so short that the muscle stem cells are probably exhausted. Due to the DMD, their muscle stem cells are constantly repairing themselves, which means the telomeres are getting shorter at an accelerated rate, much earlier in life. Future therapies that prevent telomere loss and keep muscle stem cells viable might be able to slow the progress of disease and boost muscle regeneration in the patients.”

With these new insights, Mourkioti and his team believe that targeting muscle stem cells before their telomeres become too short is a good path to pursue for developing new treatments for DMD.

“We are now looking for signaling pathways that affect telomere length in muscle stem cells, so that in principle we can develop drugs to block those pathways and maintain telomere length.”

Making Motor Neurons from Skin.

Skin cells and brain cells are like apples and oranges, they look completely different and have different functions. However, in the past decade, researchers have developed methods to transform skin cells into neurons to study neurodegenerative disorders and develop new strategies to treat brain diseases.

Scientists at Washington University School of Medicine in St. Louis published new findings on this topic yesterday in the journal Cell Stem Cell. In a nut shell, the team discovered that a specific combination of microRNAs (molecules involved in regulating what genes are turned on and off) and transcription factors (proteins that also regulate gene expression) can turn human skin cells into motor neurons, which are the brain cells that degenerate in neurodegenerative diseases like ALS, also known as Lou Gehrig’s disease.

Human motor neurons made from skin. (Credit: Daniel Abernathy)

This magical cocktail of factors told the skin cells to turn off genes that make them skin and turn on genes that transformed them into motor neurons. The scientists used skin cells from healthy individuals but will soon use their method to make motor neurons from patients with ALS and other motor neuron diseases. They are also interested in generating neurons from older patients who are more advanced in their disease. Andrew Yoo, senior author on the study, explained in a news release,

“In this study, we only used skin cells from healthy adults ranging in age from early 20s to late 60s. Our research revealed how small RNA molecules can work with other cell signals called transcription factors to generate specific types of neurons, in this case motor neurons. In the future, we would like to study skin cells from patients with disorders of motor neurons. Our conversion process should model late-onset aspects of the disease using neurons derived from patients with the condition.”

This research will make it easier for other scientists to grow human motor neurons in the lab to model brain diseases and potentially develop new treatments. However, this is still early stage research and more work should be done to determine whether these transformed motor neurons are the “real deal”. A similar conclusion was shared by Julia Evangelou Strait, the author of the Washington University School of Medicine news release,

“The converted motor neurons compared favorably to normal mouse motor neurons, in terms of the genes that are turned on and off and how they function. But the scientists can’t be certain these cells are perfect matches for native human motor neurons since it’s difficult to obtain samples of cultured motor neurons from adult individuals. Future work studying neuron samples donated from patients after death is required to determine how precisely these cells mimic native human motor neurons.”

Students Today, Scientists Tomorrow.

What did you want to be when you were growing up? For Benjamin Nittayo, a senior at Cal State University Los Angeles, it was being a scientist researching a cure for acute myeloid leukemia (AML), a form of blood cancer that took his father’s life. Nittayo is making his dream into a reality by participating in a summer research internship through the Eugene and Ruth Roberts Summer Student Academy at the City of Hope in Duarte California.

Nittayo has spent the past two summers doing cancer research with scientists at the Beckman Research Institute at City of Hope and hopes to get a PhD in immunology to pursue his dream of curing AML. He explained in a City of Hope news release,

“I want to carry his memory on through my work. Being in this summer student program helped me do that. It influenced the kind of research I want to get into as a scientist and it connected me to my dad. I want to continue the research I was able to start here so other people won’t have to go through what I went through. I don’t wish that on anybody.”

The Roberts Academy also hosts high school students who are interested in getting their first experience working in a lab. Some of these students are part of CIRM’s high school educational program Summer Program to Accelerate Regenerative Medicine Knowledge or SPARK. The goal of SPARK is to train the next generation of stem cell scientists in California by giving them hands-on training in stem cell research at leading institutes in the state.

This year, the City of Hope hosted the Annual SPARK meeting where students from the seven different SPARK programs presented their summer research and learned about advances in stem cell therapies from City of Hope scientists.

Ashley Anderson, a student at Mira Costa High School in Manhattan Beach, had the honor of giving the City of Hope SPARK student talk. She shared her work on Canavan’s disease, a progressive genetic disorder that damages the brain’s nerve cells during infancy and can cause problems with movement and muscle weakness.

Under the guidance of her mentor Yanhong Shi, Ph.D., who is a Professor of Developmental and Stem Cell Biology at City of Hope, Ashley used induced pluripotent stem cells (iPSCs) from patients with Canavan’s to generate different types of brain cells affected by the disease. Ashley helped develop a protocol to make large quantities of neural progenitor cells from these iPSCs which the lab hopes to eventually use in clinical trials to treat Canavan patients.

Ashley has always been intrigued by science, but thanks to SPARK and the Roberts Academy, she was finally able to gain actual experience doing science.

“I was looking for an internship in biosciences where I could apply my interest in science more hands-on. Science is more than reading a textbook, you need to practice it. That’s what SPARK has done for me. Being at City of Hope and being a part of SPARK was amazing. I learned so much from Dr. Shi. It’s great to physically be in a lab and make things happen.”

You can read more about Ashley’s research and those of other City of Hope SPARK students here. You can also find out more about the educational programs we fund on our website and on our blog (here and here).

Hearts and brains are center stage at CIRM Patient Advocate event

Describing the work of a government agency is not the most exciting of topics. Books on the subject would probably be found in the “Self-help for Insomniacs” section of a good bookstore (there are still some around). But at CIRM we are fortunate. When we talk about what we do, we don’t talk about the mechanics of our work, we talk about our mission: accelerating stem cell therapies to people with unmet medical needs.

Yesterday at the Gladstone Institutes in San Francisco we did just that, talking about the progress being made in stem cell research to an audience of friends, supporters and patient advocates. We had a lot to talk about, including the 35 clinical trials we have funded so far, and our goals and hopes for the future.

We were lucky to have Dr. Deepak Srivastava and Dr. Steve Finkbeiner from Gladstone join us to talk about their work. Some people are good scientists, some are good communicators. Deepak and Steve are great scientists and equally great communicators.

Deepak Srivastava highlighted ongoing stem cell research at the Gladstone
(Photo: Todd Dubnicoff/CIRM)

Deepak is the Director of the Roddenberry Stem Cell Center at Gladstone (and yes, it’s named after Gene Roddenberry of Star Trek fame) and an expert on heart disease. He talked about how advances in research have enabled us to turn heart scar tissue cells into new heart muscle cells, creating the potential to use a person’s own cells to help them recover from a heart attack.

“If you have a heart attack, your heart turns that muscle into scar tissue which affects the heart’s ability to pump blood around the body. We identified a combination of factors that support cells that are already in your heart and we have found a way of converting those scar cells into muscle. This could help repair the heart enough so you may not need a transplant, but you can lead a much more normal life.”

He said this research is now advancing to the point where they hope it could be ready for testing in people in the not too distant future and joked that his father, who has had a heart attack, volunteered to be the second person to try it. “Not the first but definitely the second.”

Steve, who is the Director of the Taube/Koret Center for Neurodegenerative Disease Research, specializes in problems in the brain; everything from Alzheimer’s and Parkinson’s to schizophrenia and ALS (also known as Lou Gehrig’s disease.

He talked about his uncle, who has end stage Parkinson’s disease, and how he sees first-hand how devastating this neurodegenerative disease is, and how that personal connection helps motivate him to work ever harder.

He talked about how so many therapies that look promising in mice fail when they are tested in people:

“A huge motivation for me has been to try and figure out a more reliable way to test these potential therapies and to move discoveries from the lab and into clinical trials in patients.”

Steve is using ordinary skin cells or tissue samples, taken from people with Parkinson’s and Alzheimer’s and other neurological conditions, and using the iPSC technique developed by Shinya Yamanaka (who is a researcher at Gladstone and also Director of CIRA in Japan) turns them into the kinds of cells found in the brain. These cells then enable him to study how these different diseases affect the brain, and come up with ways that might stop their progress.

Steve Finkbeiner is using human stem cells to model brain diseases
(Photo: Todd Dubnicoff/CIRM)

He uses a robotic microscope – developed at Gladstone – that allows his team to study these cells and test different potential therapies 24 hours a day, seven days a week. This round-the-clock approach will hopefully help speed up his ability to find something that help patients.

The CIRM speakers – Dr. Maria Millan, our interim President and CEO – and Sen. Art Torres (ret.) the Vice Chair of our Board and a patient advocate for colorectal cancer – talked about the progress we are making in helping push stem cell research forward.

Dr. Millan focused on our clinical trial work and how our goal is to create a pipeline of promising projects from the work being done by researchers like Deepak and Steve, and move those out of the lab and into clinical trials in people as quickly as possible.

Sen. Art Torres (Ret.)
(Photo: Todd Dubnicoff/CIRM)

Sen. Torres focused on the role of the patient advocate at CIRM and how they help shape and influence everything we do, from the Board’s deciding what projects to support and fund, to our creating Clinical Advisory Panels which involve a patient advocate helping guide clinical trial teams.

The event is one of a series that we hold around the state every year, reporting back to our friends and supporters on the progress being made. We feel, as a state agency, that we owe it to the people of California to let them know how their money is being spent.

We are holding two more of these events in the near future, one at UC Davis in Sacramento on October 10th, and one at Cedars-Sinai Medical Center in Los Angeles on October 30th.