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CIRM Stem Cell Blog
Tremors, muscle stiffness, shuffling, slow movement, loss of balance. These are all symptoms of Parkinson’s disease (PD), a neurodegenerative disorder that progressively destroys the dopamine-producing neurons in the brain that control movement.
While there is no cure for Parkinson’s disease, there are drugs like Levodopa and procedures like deep brain stimulation that alleviate or improve some Parkinsonian symptoms. What they don’t do, however, is slow or reverse disease progression.
Scientists are still trying to figure out what causes Parkinson’s patients to lose dopaminergic neurons, and when they do, they hope to stop the disease in its early stages before it can cause the debilitating symptoms mentioned above. In the meantime, some researchers see hope for treating Parkinson’s in the form of stem cell therapies that can replace the brain cells that are damaged or lost due to the disease.
Promising results in monkeys
This week, a team of Japanese scientists reported in the journal Nature that they treated monkeys with Parkinson’s-like symptoms by transplanting dopaminergic neurons made from human stem cells into their brains. To prevent the monkeys from rejecting the human cells, they were treated with immunosuppressive drugs. These transplanted neurons survived for more than two years without causing negative side effects, like tumor growth, and also improved PD symptoms, making it easier for the monkeys to move around.
The neurons were made from induced pluripotent stem cells (iPSCs), which are stem cells that can become any cell type in the body and are made by transforming mature human cells, like skin, back to an embryonic-like state. The scientists transplanted neurons made from the iPSCs of healthy people and PD patients into the monkeys and saw that both types of neurons survived and functioned properly by producing dopamine in the monkey brains.
Experts in the field spoke to the importance of these findings in an interview with Nature News. Anders Bjorklund, a neuroscientist at Lund University in Sweden, said “it’s addressing a set of critical issues that need to be investigated before one can, with confidence, move to using the cells in humans,” while Lorenz Studer, a stem-cell scientist at the Memorial Sloan Kettering Cancer Center in New York City, said that “there are still issues to work out, such as the number of cells needed in each transplant procedure. But the latest study is ‘a sign that we are ready to move forward.’”
Next stop, human trials
Looking ahead, Jun Takahashi, the senior author on the study, explained that his team hopes to launch a clinical trial testing this iPSC-based therapy by the end of 2018. Instead of developing personalized iPSC therapies for individual PD patients, which can be time consuming and costly, Takahashi plans to make special donor iPSC lines (called human leukocyte antigen or HLA-homozygous iPSCs) that are immunologically compatible with a larger population of patients.
In a separate study published at the same time in Nature Communications, Takahashi and colleagues showed that transplanting neurons derived from immune-matched monkey iPSCs improved their survival and dampened the immune response.
The Nature News article does a great job highlighting the findings and significance of both studies and also mentions other research projects using stem cells to treat PD in clinical trials.
“Earlier this year, Chinese researchers began a Parkinson’s trial that used a different approach: giving patients neural-precursor cells made from embryonic stem cells, which are intended to develop into mature dopamine-producing neurons. A year earlier, in a separate trial, patients in Australia received similar cells. But some researchers have expressed concerns that the immature transplanted cells could develop tumour-causing mutations.
Meanwhile, researchers who are part of a Parkinson’s stem-cell therapy consortium called GForce-PD, of which Takahashi’s team is a member, are set to bring still other approaches to the clinic. Teams in the United States, Sweden and the United Kingdom are all planning trials to transplant dopamine-producing neurons made from embryonic stem cells into humans. Previously established lines of embryonic stem cells have the benefit that they are well studied and can be grown in large quantities, and so all trial participants can receive a standardized treatment.”
For a list of projects CIRM is funding on Parkinson’s disease, visit our website.
From trauma to treatment: a Patient Advocate’s journey from helping her son battle a deadly disease to helping others do the same
For every clinical trial CIRM funds we create a Clinical Advisory Panel or CAP. The purpose of the CAP is to make recommendations and provide guidance and advice to both CIRM and the Project Team running the trial. It’s part of our commitment to doing everything we can to help make the trial a success and get therapies to the people who need them most, the patients.
Each CAP consists of three to five members, including a Patient Advocate, an external scientific expert, and a CIRM Science Officer.
Having a Patient Advocate on a CAP fills a critical need for insight from the patient’s perspective, helping shape the trial, making sure that it is being carried out in a way that has the patient at the center. A trial designed around the patient, and with the needs of the patient in mind, is much more likely to be successful in recruiting and retaining the patients it needs to see if the therapy works.
One of the clinical trials we are currently funding is focused on severe combined immunodeficiency disease, or SCID. It’s also known as “bubble baby” disease because children with SCID are born without a functioning immune system, so even a simple virus or infection can prove fatal. In the past some of these children were kept inside sterile plastic bubbles to protect them, hence the name “bubble baby.”
Anne Klein is the Patient Advocate on the CAP for the CIRM-funded SCID trial at UCSF and St. Jude Children’s Research Hospital. Her son Everett was born with SCID and participated in this clinical trial. We asked Anne to talk about her experience as the mother of a child with SCID, and being part of the research that could help cure children like Everett.
“When Everett was born his disease was detected through a newborn screening test. We found out he had SCID on a Wednesday, and by Thursday we were at UCSF (University of California, San Francisco). It was very sudden and quite traumatic for the family, especially Alden (her older son). I was abruptly taken from Alden, who was just two and a half years old at the time, for two months. My husband, Brian Schmitt, had to immediately drop many responsibilities required to effectively run his small business. We weren’t prepared. It was really hard.”
(Everett had his first blood stem cell transplant when he was 7 weeks old – his mother Anne was the donor. It helped partially restore his immune system but it also resulted in some rare, severe complications as a result of his mother’s donor cells attacking his body. So when, four years later, the opportunity to get a stem cell therapy came along Anne and her husband, Brian, decided to say yes. After some initial problems following the transplant, Everett seems to be doing well and his immune system is the strongest it has ever been.)
“It’s been four years, a lot of ups and downs and a lot of trauma. But it feels like we have turned a corner. Everett can go outside now and play, and we’re hanging out more socially because we no longer have to be so concerned about him being exposed to germs or viruses.
His doctor has approved him to go to daycare, which is amazing. So, Everett is emerging into the “normal” world for the first time. It’s nerve wracking for us, but it’s also a relief.”
How Anne came to be on the CAP
“Dr. Cowan from UCSF and Dr. Malech from the NIH (National Institutes of Health) reached out to me and asked me about it a few months ago. I immediately wanted to be part of the group because, obviously, it is something I am passionate about. Knowing families with SCID and what they go through, and what we went through, I will do everything I can to help make this treatment more available to as many people as need it.
I can provide insight on what it’s like to have SCID, from the patient perspective; the traumas you go through. I can help the doctors and researchers understand how the medical community can be perceived by SCID families, how appreciative we are of the medical staff and the amazing things they do for us.
I am connected to other families, both within and outside of the US, affected by this disease so I can help get the word out about this treatment and answer questions for families who want to know. It’s incredibly therapeutic to be part of this wider community, to be able to help others who have been diagnosed more recently.”
The CAP Team
“They were incredibly nice and when I did speak they were very supportive and seemed genuinely interested in getting feedback from me. I felt very comfortable. I felt they were appreciative of the patient perspective.
I think when you are a research scientist in the lab, it’s easy to miss the perspective of someone who is actually experiencing the disease you are trying to fix.
At the NIH, where Everett had his therapy, the stem cell lab people work so hard to process the gene corrected cells and get them to the patient in time. I looked through the window into the hall when Everett was getting his therapy and the lab staff were outside, in their lab coats, watching him getting his new cells infused. They wanted to see the recipient of the life-saving treatment that they prepared.
It is amazing to see the process that the doctors go through to get treatments approved. I like being on the CAP and learning about the science behind it and I think if this is successful in treating others, then that would be the best reward.”
“We still have to fly back to the NIH, in Bethesda, MD, every three months for checkups. We’ll be doing this for 15 years, until Everett is 18. It will be less frequent as Everett gets older but this kind of treatment is so new that it’s still important to do this kind of follow-up. In between those trips we go to UCSF every month, and Kaiser every 1-3 weeks, sometimes more.
I think the idea of being “cured”, when you have been through this, is a difficult thing to think about. It’s not a word I use lightly as it’s a very weighted term. We have been given the “all clear” before, only to be dealt setbacks later. Once he’s in school and has successfully conquered some normal childhood illnesses, both Brian and I will be able to relax more.
One of Everett’s many doctors once shared with me that, in the past, he sometimes had to tell parents of very sick children with SCID that there was nothing else they could do to help them. So now to have a potential treatment like this, he was so excited about a stem cell therapy showing such promise.
One thing we think about Everett and Alden, is that they are both so young and have been through so much already. I’m hoping that they can forget all this and have a chance to grow up and lead a normal life.”
2017 has been an exciting year for Asterias Biotherapeutics’ clinical trial which is testing a stem cell-based therapy for spinal cord injury. We’ve written several stories about patients who have made remarkable recoveries after participating in the trial (here and here).
But that doesn’t mean researchers at other companies or institutes who are also investigating spinal cord injury will be closing up shop. There’s still a long way to go with the Asterias trial and there’s still a lot to be learned about the cellular and molecular mechanisms of spinal cord injury repair, which could lead to alternative options for victims. Continued studies will also provide insights on optimizing the methods and data collection used in future clinical trials.
In fact, this week a team of UC San Diego scientists report in the Journal of Clinical Investigation that, based on brain stem cell transplant studies in a rat model of spinal cord injury, recovery continues long after the cell therapy is injected. These findings suggest that collecting clinical trial data too soon may give researchers the false impression that their therapy is not working as well as they had hoped.
In this study, funded in part by CIRM, the researchers examined brain stem cells – or neural stem cells, in lab lingo – that were derived from human embryonic stem cells. These neural stem cells (NSCs) aren’t fully matured and give rise to nerve cells as well as support cells called glia. Previous studies have shown that when NSCs are transplanted into rodent models of spinal cord injury, the cells mature into nerve cells, make connections with nerves within the animal and can help restore some limb movement.
But the timeline for the maturation of the NSCs after transplantation into the injury site wasn’t clear because most studies only measured recovery for a few weeks or months. To get a clearer picture, the UCSD team analyzed the fate and impact of human NSCs in adult rats with spinal cord injury from 1 month to 1.5 years – the longest time such an experiment has been carried out so far. The results confirmed that the transplanted NSCs did indeed survive through the 18-month time point and led to recovery of movement in the animals’ limbs.
To their surprise, the researchers found that the NSCs continued to mature and some cell types didn’t fully specialize until 6 months or even 12 months after the transplantation. This timeline suggests that although the human cells are placed into the hostile environment of an injury site in an animal model, they still follow a maturation process seen during human development.
The researchers also focused on the fate of the nerve cells’ axons, the long, thin projections that relay nerve signals and make connections with other nerve cells. Just as is seen with normal human development, these axons were very abundant early in the experiment but over several months they went through a pruning process that’s critical for healthy nerve function.
Altogether, these studies provide evidence that waiting for the clinical trial results of stem cell-based spinal cord injury therapies will require an extra dose of patience. Team lead, Dr. Mark Tuszynski, director of the UC San Diego Translational Neuroscience Institute, summed it up this way in a press release:
“The bottom line is that clinical outcome measures for future trials need to be focused on long time points after grafting. Reliance on short time points for primary outcome measures may produce misleadingly negative interpretation of results. We need to take into account the prolonged developmental biology of neural stem cells. Success, it would seem, will take time.”
Just when you thought puppies couldn’t get any cuter, this video appears in your twitter feed.
These adorable English bulldog puppies are named Darla and Spanky, and they were born with a birth defect called spina bifida where the bones and tissue surrounding the spinal cord fail to fuse completely. Spina bifida occurs in 1500-2000 children in the US each year and can cause serious problems such as paralysis and issues with walking, cognition, and bladder or bowel control. Dogs born with this condition usually cannot use their hind legs, and as a sad consequence, are typically put down at a young age.
Cutting edge research from UC Davis is now giving these unfortunate puppies hope. Diana Farmer, a fetal surgeon at UC Davis Health, and scientists from the university’s Veterinary Institute for Regenerative Cures have developed a combination surgery and stem cell transplant, using placenta-derived mesenchymal stromal cells (PMSCs), to treat puppies with spina bifida. Because prenatal screening for spina bifida is not done in dogs, Darla and Spanky received the treatment when they were ten weeks old.
With funding from a CIRM preclinical development award, Farmer has done similar surgeries in lambs that are still in the womb. A UC Davis news release provided historical background on Farmer’s work on spina bifida,
“Farmer pioneered the use of surgery prior to birth to improve brain development in children with spina bifida. She later showed that prenatal surgery combined with human placenta-derived mesenchymal stromal cells (PMSCs), held in place with a cellular scaffold, helped research lambs born with the disorder walk without noticeable disability.”
As you can see from the video, the surgeries were a success. Darla and Spanky are now able to live up to their full puppy potential and will live happily ever after with their adoptive family in New Mexico.
Looking forward, Farmer and her team would like to treat more dogs with spina bifida so they can improve another negative consequence of spina bifida called incontinence, or an uncontrollable bladder. The UC Davis release explained that, “while Darla and Spanky are very mobile and doing well on their feet, they still require diapers.” (Side note: this video proves that puppies can make anything look cute, even dirty diapers.)
Additionally, the team is hoping to receive regulatory approval from the US Food and Drug Administration to launch a clinical trial testing this therapy in humans. If this stem cell treatment proves to be both safe and effective in clinical trials, it could potentially prevent spina bifida from ever happening in animals and in humans.
Stem cell stories that caught our eye: bubble baby therapy a go in UK, in-utero stem cell trial and novel heart disease target
There were lots of CIRM mentions in the news this week. Here are two brief recaps written by Karen Ring to get you up to speed. A third story by Todd Dubnicoff summarizes an promising finding related to heart disease by researchers in Singapore.
CIRM-funded “bubble baby” disease therapy gets special designation by UK.
Orchard Therapeutics, a company based in the UK and the US, is developing a stem cell-based gene therapy called OTL-101 to treat a primary immune disease called adenosine-deaminase deficient severe combined immunodeficiency (ADA-SCID), also known as “bubble baby disease”. CIRM is funding a Phase 1/2 clinical trial led by Don Kohn of UCLA in collaboration with Orchard and the University College in London.
In July, the US Food and Drug Administration (FDA) awarded OTL-101 Rare Pediatric Disease Designation (read more about it here), which makes the therapy eligible for priority review by the FDA, and could give it a faster route to being made more widely available to children in need.
On Tuesday, Orchard announced further good news that OTL-101 received “Promising Innovative Medicine Designation” by the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA). In a news release, the company explained how this designation bodes well for advancing OTL-101 from clinical trials into patients,
“The designation as Promising Innovative Medicine is the first step of a two-step process under which OTL-101 can benefit from the Early Access to Medicine Scheme (“EAMS”). Nicolas Koebel, Senior Vice President for Business Operations at Orchard, added: “With this PIM designation we can potentially make OTL-101 available to UK patients sooner under the Early Access to Medicine Scheme”.
CIRM funded UCSF clinical trial mentioned in SF Business Times
Ron Leuty, reporter at the San Francisco Business Times, published an article about a CIRM-funded trial out of UCSF that is targeting a rare genetic blood disease called alpha thalassemia major, describing it as, “The world’s first in-utero blood stem cell transplant, soon to be performed at the University of California, San Francisco, could point the way toward pre-birth cures for a range of blood diseases, such as sickle cell disease.”
Alpha Thalassemia affects the ability of red blood cells to carry oxygen because of a reduction in a protein called hemoglobin. The UCSF trial, spearheaded by UCSF Pediatric surgeon Dr. Tippi MacKenzie, is hoping to use stem cells from the mother to treat babies in the womb to give them a better chance at surviving after birth.
In an interview with Leuty, Tippi explained,
“Our goal is to put in enough cells so the baby won’t need another transplant. But even if we fall short, if we can just establish 1 percent maternal cells circulating in the child, it will establish tolerance and then they can get the booster transplant.”
She also emphasized the key role that CIRM funded played in the development and launch of this clinical trial.
“CIRM is about more than funding for studies, MacKenzie said. Agency staff has provided advice about how to translate animal studies into work in humans, she said, as well as hiring an FDA consultant, writing an investigational new drug application and setting up a clinical protocol.”
“I’m a clinician, but running a clinical trial is different,” MacKenzie said. “CIRM’s been incredibly helpful in helping me navigate that.”
Heart, heal thyself: the story of Singheart
When you cut your finger or scrape a knee, a scab forms, allowing the skin underneath to regenerate and repair itself. The heart is not so lucky – it has very limited self-healing abilities. Instead, heart muscle cells damaged after a heart attack form scar tissue, making each heart beat less efficient. This condition can lead to chronic heart disease, the number one killer of both men and women in the US.
Research has shown that newborn mice retain the ability to completely regenerate and repair injuries to the heart because their heart muscle cells, or cardiomyocytes, are still able to divide and replenish damaged cells. But by adulthood, the mouse cardiomyocytes lose the ability to stimulate the necessary cell division processes. A research team in Singapore wondered what was preventing cardiomyocytes cell division in adult mice and if there was some way to lift that block.
This week in Nature Communications, they describe the identification of a molecule they call Singheart that may be the answer to their questions. Using tools that allow the analysis of gene activity in single cells revealed that a rare population of diseased cardiomyocytes are able to crank up genes related to cell division. And further analysis showed Singheart, a specialized genetic molecule called a long non-coding RNA, played a role in blocking this cell division gene.
As lead author Dr. Roger Foo, a principal investigator at Genome Institute of Singapore (GIS) and the National University Health System (NUHS), explained in a press release, these findings may lead to new self-healing strategies for heart disease,
“There has always been a suspicion that the heart holds the key to its own healing, regenerative and repair capability. But that ability seems to become blocked as soon as the heart is past its developmental stage. Our findings point to this potential block that when lifted, may allow the heart to heal itself.”
Confusion is not a state of mind that we usually seek out. Being bewildered is bad enough when it happens naturally, so why would anyone actively pursue it? But now some researchers are doing just that, using confusion to not just block a deadly blood cancer, but to kill it.
Today the CIRM Board approved an investment of $18.29 million to Dr. Thomas Kipps and his team at UC San Diego to use a one-two combination approach that we hope will kill Chronic Lymphocytic Leukemia (CLL).
This approach combines two therapies, cirmtuzumab (a monoclonal antibody developed with CIRM funding, hence the name) and Ibrutinib, a drug that has already been approved by the US Food and Drug Administration (FDA) for patients with CLL.
As Dr. Maria Millan, our interim President and CEO, said in a news release, the need for a new treatment is great.
“Every year around 20,000 Americans are diagnosed with CLL. For those who have run out of treatment options, the only alternative is a bone marrow transplant. Since CLL afflicts individuals in their 70’s who often have additional medical problems, bone marrow transplantation carries a higher risk of life threatening complications. The combination approach of cirmtuzumab and Ibrutinib seeks to offer a less invasive and more effective alternative for these patients.”
Ibrutinib blocks signaling pathways that leukemia cells need to survive. Disrupting these pathways confuses the leukemia cell, leading to its death. But even with this approach there are cancer stem cells that are able to evade Ibrutinib. These lie dormant during the therapy but come to life later, creating more leukemia cells and causing the cancer to spread and the patient to relapse. That’s where cirmtuzumab comes in. It works by blocking a protein on the surface of the cancer stem cells that the cancer needs to spread.
It’s hoped this one-two punch combination will kill all the cancer cells, increasing the number of patients who go into complete remission and improve their long-term cancer control.
In an interview with OncLive, a website focused on cancer professionals, Tom Kipps said Ibrutinib has another advantage for patients:
“The patients are responding well to treatment. It doesn’t seem like you have to worry about stopping therapy, because you’re not accumulating a lot of toxicity as you would with chemotherapy. If you administered chemotherapy on and on for months and months and years and years, chances are the patient wouldn’t tolerate that very well.”
The CIRM Board also approved $5 million for Angiocrine Bioscience Inc. to carry out a Phase 1 clinical trial testing a new way of using cord blood to help people battling deadly blood disorders.
The standard approach for this kind of problem is a bone marrow transplant from a matched donor, usually a family member. But many patients don’t have a potential donor and so they often have to rely on a cord blood transplant as an alternative, to help rebuild and repair their blood and immune systems. However, too often a single cord blood donation does not have enough cells to treat an adult patient.
Angiocrine has developed a product that could help get around that problem. AB-110 is made up of cord blood-derived hematopoietic stem cells (these give rise to all the other types of blood cell) and genetically engineered endothelial cells – the kind of cell that lines the insides of blood vessels.
This combination enables the researchers to take cord blood cells and greatly expand them in number. Expanding the number of cells could also expand the number of patients who could get these potentially life-saving cord blood transplants.
These two new projects now bring the number of clinical trials funded by CIRM to 35. You can read about the other 33 here.
A researcher’s data is only as good as the experimental techniques used to obtain those results. And a Stanford University study published yesterday in Cell Reports, calls into question the accuracy of a widely used method in mice that helps scientists gauge the human immune system’s response to stem cell-based therapies. The findings, funded in part by CIRM, urge a healthy dose of caution before using promising results from these mouse experiments as a green light to move on to human clinical trials.
Immune rejection of stem cell-based products is a major obstacle to translating these therapies from cutting-edge research into everyday treatments for the general population for people. If the genetic composition between the transplanted cells and the patient are mismatched, the patient’s immune system will see that cell therapy as foreign and will attack it. Unlike therapies derived from embryonic stem cells or from another person, induced pluripotent stem cells (iPSC) are exciting because scientists can potentially develop stem cell-based therapies from a patient’s own cells which relieves most of the immune rejection fears.
But manufacturing iPSC-derived therapies for each patient can take months, not to mention a lot of money, to complete. Some patients with life-threatening conditions like a heart attack or stroke don’t have the luxury of waiting that long. So even with these therapies, many researchers are working towards developing non-matched cell products which would be available “off-the-shelf. In all of these cases, immune-suppressing drugs would be needed which have their own set of concerns due to dangerous side effects, like serious infection or cancer. So, before testing in humans begins, it’s important to be able to test various immune-suppressing drugs and doses in animals to understand how well a stem cell-based therapy will survive once transplanted.
But how do you test a human immune response to a human cell product in an animal? Believe it or not, researchers – some of whom are authors in this Cell Reports publication – developed “humanized mice” back in the 1980’s. These mice were engineered to lack their own immune system to allow the engraftment of a human immune system. Over the years, advances in this mouse experimental system has gotten it closer and closer to imitating a human immune system response to transplantation of mismatched cell product.
Close but no cigar, it seems.
The team in the current study performed a detailed analysis of the immune response in two different strains of humanized mice. Both groups of animals did not mount a normal, healthy immune response and so they could not completely reject transplants of various human stem cells or stem cell-based products. Now, if you didn’t know about the abnormally weak immune response in these humanized mice, you might conclude that very little immunosuppression would be needed for a given cell therapy to keep a patient’s immune system in check. But conclusively making that interpretation is not possible, according to team lead Dr. Joseph Wu, director of Stanford’s Cardiovascular Institute:
“In an ideal situation, these humanized mice would reject foreign stem cells just as a human patient would”, he said in a press release. “We could then test a variety of immunosuppressive drugs to learn which might work best in patients, or to screen for new drugs that could inhibit this rejection. We can’t do that with these animals.”
To uncover what was happening, the team took a step back and, rather than engrafting a human immune system into the mice, they engrafted immune cells from an unrelated mouse strain. Think of it as a mouse-ified mouse, if you will. When mouse iPSCs or human embryonic stem cells were transplanted into these mouse, the engrafted mouse immune system effectively rejected the stem cells. So, compared to these mice, some elements of the immune system in the humanized mouse strains are not quite capturing the necessary complexity to truly reproduce a human immune response.
More work will be needed to understand the underlying mechanisms of this difference. Other experiments in this study suggest that signals that inhibit the immune response may be elevated in the humanized mouse models. Dr. Leonard Shultz, a pioneer in the development of humanized mice at Jackson Laboratory and an author of this study, is optimistic about building a better model:
“The immune system is highly complex and there still remains much we need to learn. Each roadblock we identify will only serve as a landmark as we navigate the future. Already, we’ve seen recent improvements in humanized mouse models that foster enhancement of human immune function.”
Until then, the team urges other scientists to tread carefully when drawing conclusions from the humanized mice in use today.
Did you take your vitamins today? It’s not always easy to remember with such busy lives, but after you read this blog, you’ll be sure to make vitamins part of your daily routine if you haven’t already!
Two recent studies, published in the journals Nature and Cell, reported that vitamin C has a direct impact on the function of blood forming, or hematopoietic stem cells, and can be used to protect mice from getting a blood cancer called leukemia.
Science reporter Bradley Fikes compared the findings of the two studies yesterday in the San Diego Union Tribune. According to Fikes, the Nature study, which was conducted by scientists at UT Southwestern, “found that human and mouse hematopoietic stem cells absorb unusually large amounts of vitamin C. When the cells were depleted of vitamin C, they were more likely to turn into leukemia cells.”
As for the Cell study, scientists from NYU Langone Health “found that high doses of vitamin C can cause leukemic cells to die, potentially making it a useful and safe chemotherapy agent.” For more details on this particular study, see our blog from last week and the video below.
Dr. Benjamin Neel, director of NYU Langone’s Perlmutter Cancer Center, discusses how vitamin C may “tell” faulty stem cells in the bone marrow to mature and die normally, instead of multiplying to cause blood cancers.
Vitamin C levels are crucial for preventing leukemia
The common factor between the two studies is a gene called Tet2, which is turned on in blood stem cells and protects them from over-proliferating and acquiring genetic mutations that transform them into leukemia cells. If one copy of the Tet2 gene is genetically mutated, treating blood stem cells with vitamin C can make up for this partial loss in Tet2 function. However, if both copies of Tet2 are mutated, its protective functions are completely lost and blood stem cells can turn cancerous.
Fikes reached out to Sean Morrison, senior author on the Nature study, for an explanation about the relationship between vitamin C and Tet2, and how it can be leveraged to prevent or treat leukemia:
“The Cell study showed that high doses of vitamin C can compensate for Tet2 mutations, restoring normal function, Morrison said. Usually, transformation of normal cells into leukemic cells is irreversible, but the study demonstrated that’s not true when the leukemia is driven by Tet2 mutations.”
“The Nature study demonstrated that vitamin C is a limiting factor in the proper function of Tet2, Morrison said. People have two copies of the gene, one from each parent. When one of the genes is disabled, it’s important to take the full recommended dose of vitamin C so the remaining gene can exert its full tumor-suppressing effect.”
Before you place your bulk order of vitamin C on amazon, you should be aware that Morrison and his colleagues found that giving mice super doses of the supplement failed to further reduce their risk of getting leukemia. Thus, it seems that having the right levels of vitamin C in blood stem cells and healthy copies of the Tet2 gene are vital for preventing leukemia.
Vitamin C, a panacea for cancer?
These two studies raise important questions. Do vitamin C levels play a role in the development of other cancer cells and could this supplement be used as a treatment for other types of cancers?
Since the 1970’s, scientists and doctors have pursued vitamin C as a potential cancer treatment. Early stage research revealed that vitamin C plays a role in slowing the growth of various types of cancer cells including prostate, colon and brain cancer cells. More recently, some of this research has progressed to clinical trials that are testing high-doses of vitamin C either by itself or in combination with chemotherapy drugs in cancer patients. Some of these trials have reported an improved quality of life and increased average survival time in patients, but more research and trials are necessary to determine whether vitamin C is a truly effective anti-cancer therapy.
Now that Morrison and his team have a better understanding of how vitamin C levels affect cancer risk, they plan to address some of these outstanding questions in future studies.
“Our data also suggest that probably not all cancers are increased by vitamin C depletion. We particularly would predict that certain leukemias would be increased in the absence of vitamin C. We’re collaborating with the Centers for Disease Control right now to look more carefully at the epidemiological data that have been collected over decades, to understand more precisely which cancers are at increased risk in people that have lower levels of vitamin C.”
Since 2010, the CIRM Bridges Program has provided paid stem cell research internships to students at California colleges and universities that don’t have major stem cell research programs. In order to keep in touch with these interns, The Stem Cellar has an ongoing CIRM Scholars blog series, inviting alumni from our training programs to reflect on the importance of their internships, to update readers on their career path and to give career advice to the current interns.
The blog below, written by Mimi Krutein from the 2011 Bridges program at Cal State University San Marcos, is based on a presentation she gave in late July at the 2017 Annual CIRM Bridges Trainee Meeting in San Diego.
The science graduate school experience is not at all what I was expecting. I imagined it as a mentally stimulating flurry of discoveries and training; before I started I pictured a cross between Harry Potter and The Magic School Bus. What I got, and what most graduate students get, is a vaguely escorted slog into a land of uncertainty and imposter syndrome, sprinkled with fleeting moments of clarity and excitement. But don’t get me wrong; it is worth it.
My personal road to graduate school was quite unorthodox. I entered California State University San Marcos (CSUSM) as a nursing major, because I had a genuine interest in medicine and was fascinated by the complexity of the human body.
It also didn’t require calculus level math, so I was sold.
I generally enjoyed my courses but everything changed for me when I took microbiology. It was my first introduction to basic science. Disease mechanisms of microorganisms blew my mind, sparked my curiosity, and catalyzed a shift in focus that never readjusted.
It was then I decided to add a biology minor to feed the beast, but didn’t have the confidence to switch majors completely. The pre-nursing program actually advised me not to add the minor; my grades at that point were good but not stellar, and they thought that the new load would be too difficult. That summer I formally applied to the CSUSM nursing program and was rejected, missing the cutoff by one point. Chalking it up to fate, I turned gracefully on my heels and belly flopped into a molecular biology major with open arms, calculus and all.
A few semesters passed and I desperately craved more lab time so I applied to 12 summer undergraduate research programs and was swiftly rejected due to lack of experience. The only position I was offered was a 100-hour, unpaid internship at a tiny biotech composed of 5 people, where we utilized bioluminescent phytoplankton to monitor water toxicity. Then I joined the only research lab at CSUSM with an opening, and under Dr. Betsy Read I studied the metabolic pathways of the model organism Emiliania huxleyi, also a phytoplankton.
As much as I loved the lab and industry training I was receiving, I wanted to integrate my fascination of human medicine with my passion for laboratory science. Betsy pulled me into her office one day and asked the very obtuse question “what do you want to do in science?” To her surprise –and slight disappointment I’m sure- I told her that I didn’t want to stay in phytoplankton, but rather explore medically relevant research, and study human disease. Happily she lit up and frantically told me about the CIRM Bridges internship that would be perfect, the caveat being that applications were due that very day. I received a 24-hour extension, and was later accepted for the 2011 program.
I was equal parts inspired and terrified
For my CIRM internship I joined Tobin Dickerson’s lab in the department of chemistry at The Scripps Research Institute. I received excellent one-on-one training in a small lab studying highly infectious agents, primarily botulinum toxin. Now, botulinum toxin has an extremely simple mechanism of action, however, it is also the most potent neurotoxin known to man. Approximately 1 gram of aerosolized toxin can kill 1 million people; and the bacteria that produces it, Clostridium botulinum, is relatively easy to propagate, making it a potential bioterrorist agent.
For this reason, The Department of Defense gave us a grant to pursue high-throughput screening of small molecule inhibitors that could block the effects of this toxin. I assisted in the screening and follow up tests on individual inhibitors. At the same time, I established a robust method for generating motor neurons from human embryonic and induced pluripotent stem cells. This work provided us with a virtually endless pool of boltulinum-sensitive cells for the use of cellular studies with prospective inhibitors found in our initial screens. Deriving the neurons from stem cells also eliminated the need for expensive and tiresome motor neuron harvests from animals. The cells I produced in the lab presented as bonafide motor neurons because they produced an appropriate dose response to live toxin.
I finally felt like a real scientist
After my internship, I was formally hired by the lab as a part time technician while I finished my last year of classes as CSUSM. My two years of work in the lab resulted in three publications, one of which was accepted for the cover of ACS Combinatorial Science. More importantly though, the years I spent in the Dickerson lab provided room for me to grow into myself as a scientist, receive unparalleled training, and gain perspective on what it meant to be in the thick of academic research.
After many discussions with my peers and mentors, I decided graduate school, ideally a PhD track, was the next step for my scientific career. I knew I loved research, but I wanted to learn how to think, how to approach unanswered questions in a productive manner. I wanted to be trained by everyone who could provide me with knowledge.
I was just plain hungry.
And like most 20-somethings on the edge of graduation, my passion was mixed in equal parts with indecisiveness. I really didn’t know what I wanted to study, but I knew I wanted to utilize my stem cell training, and I knew what made my mind light up; I was -and still am- fascinated by how diseases work on a cellular and molecular level. So, after months of searching, digging, and crosschecking, I applied to a dozen translational research programs across the US.
And then the news arrived
While running late to a class, I got the acceptance email from my dream school; the University of Washington. After reading the subject line I was frozen with disbelief, I called my mom, forgot where I was going and took a stroll the other direction until I realized I had a test waiting for me. It never occurred to me that I could actually do this for real.
My first day of grad school was one I will never forget. After a lukewarm five minutes of awkwardly chatting with my new postdoc lab members, we go out to get coffee and I proceed to faceplant in the middle of a puddle-filled crosswalk directly in front of a truck. I skinned my knee and sliced my hand open, but magically managed to keep my coffee upright. Understandably, my newly acquired lab members didn’t let me touch anything of real importance for 2 weeks. Even after being considered a ‘seasoned’ graduate student I still knock over racks of pipette tips or spill liters of E. coli cultures on my new jeans. Such is the grad school life. Part of me hopes once I earn those fancy three letters after my name, I’ll evolve to the perfect scientist, but I won’t bet on it.
To those of you considering graduate school
I’ll end with these parting thoughts. Obviously, I’m still not on the other end of this whole grad school thing, but I can tell you from the four years I’ve spent doing this so far, there has been no experience more rewarding and humbling than pursuing a PhD. If you find yourself interested in taking the leap in a similar direction, know that if you choose this path, it’s a marathon, not a sprint so take care of yourself through the process. Maintain a strong support system, both for your personal and professional well-being. Foster relationships with your peers to gain strength in numbers and build mentorships with individuals you admire to perpetuate curiosity. Choose your home lab thoughtfully; the Principal Investigator to Student dynamic is the cornerstone of the graduate school experience; you can’t be on different pages with the lab’s leader and expect to write the same story.
Imposter syndrome is the greatest barrier to your success
I spent 22 years wholeheartedly believing I couldn’t do the thing I’m currently doing, and I’ll tell you guys a secret, some days I still feel that way. But it’s vital to recognize that you are worthy of success and not defined by your failures. Lastly, find humor where you can and stay hungry for opportunities that you believe are just outside of your reach. And stay hungry for knowledge, it’s one of few things that doesn’t expire.
CIRM weekly stem cell roundup: stomach bacteria & cancer; vitamin C may block leukemia; stem cells bring down a 6’2″ 246lb football player
Stomach bacteria crank up stem cell renewal, may be link to gastric cancer.
The Centers for Disease Control and Prevention estimate that two-thirds of the world’s population is infected with H. pylori, a type of bacteria that thrives in the harsh acidic conditions of the stomach. Data accumulated over the past few decades shows strong evidence that H. pylori infection increases the risk of stomach cancers. The underlying mechanisms of this link have remained unclear. But research published this week in Nature suggests that the bacteria cause stem cells located in the stomach lining to divide more frequently leading to an increased potential for cancerous growth.
Tumors need to make an initial foothold in a tissue in order to grow and spread. But the cells of our stomach lining are replaced every four days. So, how would H. pylori bacterial infection have time to induce a cancer? The research team – a collaboration between scientists at the Max Planck Institute in Berlin and Stanford University – asked that question and found that the bacteria are also able to penetrate down into the stomach glands and infect stem cells whose job it is to continually replenish the stomach lining.
Further analysis in mice revealed that two groups of stem cells exist in the stomach glands – one slowly dividing and one rapidly dividing population. Both stem cell populations respond similarly to an important signaling protein, called Wnt, that sustains stem cell renewal. But the team also discovered a second key stem cell signaling protein called R-spondin that is released by connective tissue underneath the stomach glands. H. pylori infection of these cells causes an increase in R-spondin which shuts down the slowly dividing stem cell population but cranks up the cell division of the rapidly dividing stem cells. First author, Dr. Michal Sigal, summed up in a press release how these results may point to stem cells as the link between bacterial infection and increased risk of stomach cancer:
“Since H. pylori causes life-long infections, the constant increase in stem cell divisions may be enough to explain the increased risk of carcinogenesis observed.”
Vitamin C may have anti-blood cancer properties
Vitamin C is known to have a number of health benefits, from preventing scurvy to limiting the buildup of fatty plaque in your arteries. Now a new study says we might soon be able to add another benefit: it may be able to block the progression of leukemia and other blood cancers.
Researchers at the NYU School of Medicine focused their work on an enzyme called TET2. This is found in hematopoietic stem cells (HSCs), the kind of stem cell typically found in bone marrow. The absence of TET2 is known to keep these HSCs in a pre-leukemic state; in effect priming the body to develop leukemia. The researchers showed that high doses of vitamin C can prevent, or even reverse that, by increasing the activity level of TET2.
In the study, in the journal Cell, they showed how they developed mice that could have their levels of TET2 increased or decreased. They then transplanted bone marrow with low levels of TET2 from those mice into healthy, normal mice. The healthy mice started to develop leukemia-like symptoms. However, when the researchers used high doses of vitamin C to restore the activity levels of TET2, they were able to halt the progression of the leukemia.
Now this doesn’t mean you should run out and get as much vitamin C as you can to help protect you against leukemia. In an article in The Scientist, Benjamin Neel, senior author of the study, says while vitamin C does have health benefits, consuming large doses won’t do you much good:
“They’re unlikely to be a general anti-cancer therapy, and they really should be understood based on the molecular understanding of the many actions vitamin C has in cells.”
However, Neel says these findings do give scientists a new tool to help them target cells before they become leukemic.
Toeing the line: how unapproved stem cell treatment made matters worse for an NFL player
American football players are tough. They have to be to withstand pounding tackles by 300lb men wearing pads and a helmet. But it wasn’t a crunching hit that took Washington Redskins player Jordan Reed out of the game; all it took to put the 6’2” 246 lb player on the PUP (Physically Unable to Perform) list was a little stem cell injection.
Reed has had a lingering injury problem with the big toe on his left foot. So, during the off-season, he thought he would take care of the issue, and got a stem cell injection in the toe. It didn’t quite work the way he hoped.
In an interview with the Richmond Times Dispatch he said:
“That kind of flared it up a bit on me. Now I’m just letting it calm down before I get out there. I’ve just gotta take my time, let it heal and strengthen up, then get back out there.”
It’s not clear what kind of stem cells Reed got, if they were his own or from a donor. What is clear is that he is just the latest in a long line of athletes who have turned to stem cells to help repair or speed up recovery from an injury. These are treatments that have not been approved by the Food and Drug Administration (FDA) and that have not been tested in a clinical trial to make sure they are both safe and effective.
In Reed’s case the problem seems to be a relatively minor one; his toe is expected to heal and he should be back in action before too long.
Stem cell researcher and avid blogger Dr. Paul Knoepfler wrote he is lucky, others who take a similar approach may not be:
“Fortunately, it sounds like Reed will be fine, but some people have much worse reactions to unproven stem cells than a sore toe, including blindness and tumors. Be careful out there!”
A stem cell’s capacity to lay quiet and, when needed, to self-renew plays a key role in restoring and maintaining the health of our organs. Unfortunately, cancer stem cells possess that same property allowing them to evade radiation and chemotherapy treatments which leads to tumor regrowth. And a CIRM-funded study published today in Cell shows the deviousness of these cancer cells goes even further. The Stanford research team behind the study found evidence that brain stem cells, which normally guide brain development and maintenance, unintentionally communicate with brain cancer cells in deadly tumors, called gliomas, providing them a means to invade other parts of the brain. But the silver lining to this scary insight is that it may lead to new treatment options for patients.
High grade gliomas do not end well
The most aggressive forms of glioma are called high grade gliomas and they carry devastating prognoses. For instance, the most common form of these tumors in children has a median survival of just 9 months with a 5-year survival of less than 1%. Surgery or anti-cancer therapies may help for a while but the tumor inevitably grows back.
Researchers have observed that gliomas typically originate in the brain stem and very often invade a brain stem cell-rich area, called the subventrical zone (SVZ), that provides a space for the therapy-resistant cancer stem cells to hole up. This path of tumor spread is associated with a shorter time to relapse and poorer survival but the exact mechanism wasn’t known. The Stanford team hypothesized that SVZ brain stem cells release some factor that attracts the gliomas to preferentially invade that part of the brain.
To test this chemo-attraction idea, they mimicked cancer cell invasion in a specialized, dual compartment petri dish called a Boyden chamber. In the bottom compartment, they placed the liquid food, or media, that SVZ brain stem cells had been grown in. On the upper compartment, they placed the cancerous glioma cells. A porous, gelatin membrane between the two compartments acts as a barrier but allows the cells to receive signals from the lower compartment and migrate down into the media if a chemoattractant is present. And that’s what they saw: a significant glioma cell migration through the gelatin toward the brain stem cell media.
Pleiotrophin: an unintentional communicator with brain cancer cells
Something or somethings in the SVZ brain stem cell media had to be attracting the glioma cells. So, the Stanford team analyzed the composition of the media and identified four proteins that, when physically complexed together, had the same chemo-attraction ability as the media. They were pleased to find that one of the four proteins is pleiotrophin which is known to not only play a role in normal brain development and regeneration but also to increase glioma cell migration. And in this study, they showed that higher levels of pleiotrophin are present in the SVZ brain stem cell area compared to other regions of the brain. They went on to show that blocking the production of pleiotrophin in mice reduced the invasion of glioma cells into the SVZ region. This result suggests that blocking the release of pleiotrophin by brain stem cells in the SVZ could help prevent or slow down the spread of glioma in patients’ brains without the need of irradiating this important part of the brain.
The silver lining: hsp90 inhibitors have therapeutic promise
To further explore this potential therapeutic approach, the team examined hsp90, one of the other three proteins complexed with pleiotrophin. Though it doesn’t have chemoattractant properties, it still is a necessary component and may act to stabilize pleiotrophin. It also turns out that inhibitors for hsp90 have already been developed in the clinic for treating various cancers. When the researchers in this study blocked hsp90 production in the SVZ region of mice, they observed a reduced invasion of glioma cells. Though clinical grade hsp90 inhibitors exist, team lead Michelle Monje, MD, PhD – assistant professor of neurology, Stanford University – tells me that some tweaking of these drugs will be necessary to reach gliomas:
“Our challenge is to find an hsp90 inhibitor that penetrates the brain at effective concentrations.”
Once they find that inhibitor, it could provide new options, and hope, for people diagnosed with this dreadful cancer.
Patients and Patient Advocates are at the heart of everything we do at CIRM. That’s why we are holding three free public events in the next few months focused on updating you on the stem cell research we are funding, and our plans for the future.
Right now we have 33 projects that we have funded in clinical trials. Those range from heart disease and stroke, to cancer, diabetes, ALS (Lou Gehrig’s disease), two different forms of vision loss, spinal cord injury and HIV/AIDS. We have also helped cure dozens of children battling deadly immune disorders. But as far as we are concerned we are only just getting started.
Over the course of the next few years, we have a goal of adding dozens more clinical trials to that list, and creating a pipeline of promising therapies for a wide range of diseases and disorders.
That’s why we are holding these free public events – something we try and do every year. We want to let you know what we are doing, what we are funding, how that research is progressing, and to get your thoughts on how we can improve, what else we can do to help meet the needs of the Patient Advocate community. Your voice is important in helping shape everything we do.
The first event is at the Gladstone Institutes in San Francisco on Wednesday, September 6th from noon till 1pm. The doors open at 11am for registration and a light lunch.
Here’s a link to an Eventbrite page that has all the information about the event, including how you can RSVP to let us know you are coming.
We are fortunate to be joined by two great scientists, and speakers – as well as being CIRM grantees- from the Gladstone Institutes, Dr. Deepak Srivastava and Dr. Steve Finkbeiner.
Dr. Srivastava is working on regenerating heart muscle after it has been damaged. This research could not only help people recover from a heart attack, but the same principles might also enable us to regenerate other organs damaged by disease. Dr. Finkbeiner is a pioneer in diseases of the brain and has done ground breaking work in both Alzheimer’s and Huntington’s disease.
We have two other free public events coming up in October. The first is at UC Davis in Sacramento on October 10th (noon till 1pm) and the second at Cedars-Sinai in Los Angeles on October 30th (noon till 1pm). We will have more details on these events in the coming weeks.
We look forward to seeing you at one of these events and please feel free to share this information with anyone you think might be interested in attending.
Chia Pets make growing hair look easy. You might not be familiar with these chia plant terracotta figurines if you were born after the 80s, but I remember watching commercials growing up and desperately wanting a “Chia Pet, the pottery that grows!”
My parents eventually caved and got me a Chia teddy bear, and I was immediately impressed by how easy it was for my bear to grow “hair”. All I needed to do was to sprinkle water over the chia seeds and spread them over my chia pet, and in three weeks, voila, I had a bear that had sprouted a lush, thick coat of chia leaves.
These days, you can order Chia celebrities and even Chia politicians. If only treating hair loss in humans was as easy as growing sprouts on the top of Chia Mr. T’s head…
Activating Hair Follicle Stem Cells, the secret to hair growth?
That day might come sooner than we think thanks to a CIRM-funded study by UCLA scientists.
Published today in Nature Cell Biology, the UCLA team reported a new way to boost hair growth that could eventually translate into new treatments for hair loss. The study was spearheaded by senior authors Heather Christofk and William Lowry, both professors at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.
Christofk and Lowry were interested in understanding the biology of hair follicle stem cells (HFSCs) and how their metabolism (the set of chemical changes required for a cell to sustain itself) plays a role in hair growth. HFSCs are adult stem cells that live in the hair follicles of our skin. They are typically inactive but can quickly “wake up” and actively divide when a new hair growth cycle is initiated. When HFSCs fail to activate, hair loss occurs.
A closer look at HFSCs in mice revealed that these stem cells are dependent on the products of the glycolytic pathway, a metabolic pathway that converts the nutrient glucose into a metabolite called pyruvate, to stimulate their activation. The HFSCs have a choice, they can either give the pyruvate to their mitochondria to produce more energy, or they can break down the pyruvate into another metabolite called lactate.
The scientists found that if they tipped the balance towards producing more lactate, the HFSCs activated and induced hair growth. On the other hand, if they blocked lactate production, HFSCs couldn’t activate and new hair growth was blocked.
In a UCLA news release, Lowry explained the novel findings of their study,
“Before this, no one knew that increasing or decreasing the lactate would have an effect on hair follicle stem cells. Once we saw how altering lactate production in the mice influenced hair growth, it led us to look for potential drugs that could be applied to the skin and have the same effect.”
New drugs for hair loss?
In the second half of the study, the UCLA team went on the hunt for drugs that promote lactate production in HFSCs in hopes of finding new treatment strategies to battle hair loss. They found two drugs that boosted lactate production when applied to the skin of mice. One was called RCGD423, which activates the JAK-Stat signaling pathway and stimulates lactate production. The other drug, UK5099, blocks the entry of pyruvate into the mitochondria, thereby forcing HFSCs to turn pyruvate into lactate resulting in hair growth. The use of both drugs for boosting hair growth are covered by provisional patent applications filed by the UCLA Technology Development Group.
Aimee Flores, the first author of the study, concluded by explaining why using drugs to target the HFSC metabolism is a promising approach for treating hair loss.
“Through this study, we gained a lot of interesting insight into new ways to activate stem cells. The idea of using drugs to stimulate hair growth through hair follicle stem cells is very promising given how many millions of people, both men and women, deal with hair loss. I think we’ve only just begun to understand the critical role metabolism plays in hair growth and stem cells in general; I’m looking forward to the potential application of these new findings for hair loss and beyond.”
If these hair growth drugs pan out, scientists might give Chia Pets a run for their money.
CIRM weekly stem cell roundup: minibrain model of childhood disease; new immune insights; patient throws out 1st pitch
New human Mini-brain model of devastating childhood disease.
The eradication of Aicardi-Goutieres Syndrome (AGS) can’t come soon enough. This rare but terrible inherited disease causes the immune system to attack the brain. The condition leads to microcephaly (an abnormal small head and brain size), muscle spasms, vision problems and joint stiffness during infancy. Death or a persistent comatose state is common by early childhood. There is no cure.
Though animal models that mimic AGS symptoms are helpful, they don’t reflect the human disease closely enough to provide researchers with a deeper understanding of the mechanisms of the disease. But CIRM-funded research published this week may be a game changer for opening up new therapeutic strategies for the children and their families that are suffering from AGS.
To get a clearer human picture of the disease, Dr. Alysson Muotri of UC San Diego and his team generated AGS patient-derived induced pluripotent stem cells (iPSCs). These iPSCs were then grown into “mini-brains” in a lab dish. As described in Cell Stem Cell, their examination of the mini-brains revealed an excess of chromosomal DNA in the cells. This abnormal build up causes various toxic effects on the nerve cells in the mini-brains which, according to Muotri, had the hallmarks of AGS in patients:
“These models seemed to mirror the development and progression of AGS in a developing fetus,” said Muotri in a press release. “It was cell death and reduction when neural development should be rising.”
In turns out that the excess DNA wasn’t just a bunch of random sequences but instead most came from so-called LINE1 (L1) retroelements. These repetitive DNA sequences can “jump” in and out of DNA chromosomes and are thought to be remnants of ancient viruses in the human genome. And it turns out the cell death in the mini-brains was caused by the immune system’s anti-viral response to these L1 retroelements. First author Charles Thomas explained why researchers may have missed this in their mouse models:
“We uncovered a novel and fundamental mechanism, where chronic response to L1 elements can negatively impact human neurodevelopment. This mechanism seems human-specific. We don’t see this in the mouse.”
The team went on to test the anti-retroviral effects of HIV drugs on their AGS models. Sure enough, the drugs decreased the amount of L1 DNA and cell growth rebounded in the mini-brains. The beauty of using already approved drugs is that the route to clinical trials is much faster and in fact a European trial is currently underway.
For more details, watch this video interview with Dr. Muotri:
New findings about immune cell development may open door to new cancer treatments
For those of you who suffer with seasonal allergies, you can blame your sniffling and sneezing on an overreaction by mast cells. These white blood cells help jump start the immune system by releasing histamines which makes blood vessels leaky allowing other immune cells to join the battle to fight disease or infection. Certain harmless allergens like pollen are mistaken as dangerous and can also cause histamine release which triggers tearing and sneezing.
Dysfunction of mast cells are also involved in some blood cancers. And up until now, it was thought a protein called stem cell factor played the key role in the development of blood stem cells into mast cells. But research reported this week by researchers at Karolinska Institute and Uppsala University found cracks in that previous hypothesis. Their findings published in Blood could open the door to new cancer therapies.
The researchers examine the effects of the anticancer drug Glivec – which blocks the function of stem cell factor – on mast cells in patients with a form of leukemia. Although the number of mature mast cells were reduced by the drug, the number of progenitor mast cells were not. The progenitors are akin to teenagers in that they’re at an intermediate stage of development, more specialized than stem cells but not quite mast cells. The team went on to confirm that stem cell factor was not required for the mast cell progenitors to survive, multiply and mature. Instead, their work identified two other growth factors, interleukin 3 and 6, as important for mast cell development.
In a press release, lead author Joakim Dahlin, explained how these new insights could lead to new therapies:
“The study increases our understanding of how mast cells are formed and could be important in the development of new therapies, for example for mastocytosis for which treatment with imatinib/Glivec is not effective. One hypothesis that we will now test is whether interleukin 3 can be a new target in the treatment of mast cell-driven diseases.”
Patient in CIRM-funded trial regains use of arms, hands and fingers will throw 1st pitch in MLB game.
We end this week with some heart-warming news from Asterias Biotherapeutics. You avid Stem Cellar readers will remember our story about Lucas Lindner several weeks back. Lucas was paralyzed from the neck down after a terrible car accident. Shortly after the accident, in June of 2016, he enrolled in Asterias’ CIRM-funded trial testing an embryonic stem cell-based therapy to treat his injury. And this Sunday, August 13th, we’re excited to report that due to regaining the use of his arms, hands and fingers since the treatment, he will throw out the first pitch of a Major League Baseball game in Milwaukee. Congrats to Lucas!
For more about Lucas’ story, watch this video produced by Asterias Biotherapeutics:
High school is a transformative time for any student. It marks the transition from childhood to adulthood and requires discipline, dedication and determination to excel and get into their desired college or university.
The barrier to entry for college now seems much higher than when I was eighteen, but I am not worried for the current generation of high school students. That’s because I’ve met some of the brightest young minds this past week at the 2017 CIRM SPARK meeting.
SPARK is CIRM’s high school education program, which gives underprivileged students in California the opportunity to train as stem cell scientists for the summer. Students participate in a summer research internship at one of seven programs at leading research institutes in the state. They attend scientific lectures, receive training in basic lab techniques, and do an eight-week stem cell research project under the guidance of a mentor.
At the end of the summer, SPARK students congregate at the annual SPARK poster meeting where they present the fruits of their labor. Meeting these students in person is my favorite time of the year. Their enthusiasm for science and stem cell research is contagious. And when you engage them or listen to them talk about their project, it’s hard to remember that they are still teenagers and not graduate level scientists.
What impresses me most about these students is their communication skills. Each summer, I challenge SPARK students to share their summer research experience through social media and blogging, and each time they go above and beyond with their efforts. Training these students as effective science communicators is important to me. They are the next generation of talented scientists who can help humanize research for the public. They have the power to change the perception of science as a field to be embraced and one that should receive proper funding.
It’s also inspiring to me that this young generation can effectively educate their friends, family and the public about the importance of stem cell research and how it will help save the lives of patients who currently don’t have effective treatments. If you haven’t already, I highly recommend checking out the #CIRMSPARKlab hashtag on Instagram to get a taste of what this year’s group of students accomplished during their internships.
Asking students, many of whom are learning to do research for the first time, to post on Instagram once a week and write a blog about their internship is a tall task. And I believe with any good challenge, there should be a reward. Therefore, at this year’s SPARK meeting held at the City of Hope in Duarte, California, I handed out prizes.
It was very difficult to pick winners for our presentation, social media and blogging awards because honestly, all our students were excellent this year. Even Kevin McCormack, Director of CIRM’s Communications, who helped me read the students’ blogs said,
“This was really tough. The standard of the blogs this year was higher than ever; and previous years had already set the bar really high. It was really difficult deciding which were really good and which were really, really good.”
Ok, enough with the hype, I know you want to read these award-winning blogs so I’ve shared them below. I hope that they inspire you as much as they have inspired me.
Amira Hirara (Children’s Hospital Oakland Research Institute)
It was a day like any other. I walked into the room, just two minutes past 10:30am, ready for another adventurous day in the lab. Just as I settle down, I am greeted by my mentor with the most terrifying task I have ever been asked to perform, “Will you passage the cells for me…alone?” Sweat begins to pour down my cemented face as I consider what is at stake.
The procedure was possibly thirty steps long and I have only executed it twice, with the supervision of my mentor of course. To be asked to do the task without the accompaniment of an experienced individual was unthought-of. I feel my breath begin to shorten as I mutter the word “Ok”. Yet it wasn’t just the procedure that left me shaking like a featherless bird, it was the location of my expedition as well. The dreaded tissue culture room. If even a speck of dirt enters the circulating air of the biosafety cabinet, your cells are at risk of death…death! I’ll be a cell murderer. “Alright”, she said, “I’ll just take a look at the cells then you’ll be on your way.” As we walk down the hallway, my eyes began to twitch as I try to recall the first steps of the procedure. I remember freezing our plates with Poly-ornithine and laminin, which essentially simulates the extracellular environment and allows adhesion between the cell and the plate itself. I must first add antibiotics to rid the frozen plate of potential bacteria. Then I should remove my cells from the incubator, and replace the old solution with accutase and new media, to nourish the cells, as well as unbind them from the plate before. Passaging is necessary when the cell density gets too high, as the cells must be relocated to a roomier environment to better promote survival. As we approach the tissue culture room, my jaw unclenches, as I realize the whirlwind of ideas meant I know more than I thought. My mentor retrieves our cells, views them under the microscope, and deems them ‘ready for passaging’.
“Good luck Amira” she says to me with a reassuring smile. I enter the room ready for battle. Placing first my gloves and coat, I then spray my hands and all things placed in the cabinet with 70% ethanol, to insure a sterile work environment. Back to the procedure, I’ll place the cellular solution of accutase and media into a covalent tube. After, I’ll centrifuge it for two minutes until a cellular pellet forms at the bottom, then dissolve the cells in fresh media, check its density using a cell counter, and calculate the volume of cellular solution needed to add to my once frozen plates. Wait, once I do that, I’ll be all done. I eagerly execute all the steps, ensuring both accuracy and sterility in my work. Pride swells within me as I pipette my last milliliter of solution into my plate. The next day, my mentor and I stop by to check on how our sensitive neural stem cells are doing. “Wow Amira, I am impressed, your cells seem very confluent in their new home, great job!” I smile slyly and begin to nod my head. I now walk these hallways, with a puffed chest, brightened smile, and eagerness to learn. My stem cells did not die, and having the amazing opportunity to master their treatment and procedures, is something I can never forget.
Gaby Escobar (Stanford University)
Walking into the lab that would become my home for the next 8 weeks, my mind was an empty canvas. Up to that point, my perception of the realm of scientific research was one-sided. Limited to the monotonous textbook descriptions of experiments that were commonplace in a laboratory, I wanted more. I wanted to experience the alluring call of curiosity. I wanted to experience the flash of discovery and the unnerving drive that fueled our pursuit of the unknown. I was an empty canvas looking for its first artistic stroke.
Being part of the CIRM Research program, I was lucky enough to have been granted such opportunity. Through the patient guidance of my mentor, I was immersed into the limitless world of stem cell biology. From disease modeling to 3D bioprinting, I was in awe of the capabilities of the minds around me. The energy, the atmosphere, the drive all buzzed with an inimitable quest for understanding. It was all I had imagined and so, so much more.
However, what many people don’t realize is research is an arduous, painstaking process. Sample after sample day after day, frustration and doubt loomed above our heads as we tried to piece together a seemingly pieceless puzzle. Inevitably, I faced the truth that science is not the picture-perfect realm I had imagined it to be. Rather, it is tiring, it is relentless, and it is unforgiving. But at the same time, it is incomparably gratifying. You see, the innumerable samples, the countless gels and PCRS, all those futile attempts to fruitlessly make sense of the insensible, have meaning. As we traversed through the rollercoaster ride of our project, my mentor shared a personal outlook that struck very deeply with me: her motivation to work against obstacle after obstacle comes not from the recognition or prestige of discovering the next big cure but rather from the notion that one day, her perseverance may transform someone’s life for the good. And in that, I see the beauty of research and science: the coming together of minds and ideas and bewildering intuitions all for the greater good.
As I look back, words cannot express the gratitude I feel for the lessons I have learned. Undoubtedly, I have made countless mistakes (please don’t ask how many gels I’ve contaminated or pipettes I have dropped) but I’ve also created the most unforgettable of memories. Memories that I know I will cherish for the journey ahead of me. Having experienced the atmosphere of a vibrant scientific community, I have found a second home, a place that I can explore and question and thrive. And although not every day will hold the cure to end all diseases or hand an answer on a silver platter, every day is another opportunity. And with that, I walk away perhaps not with the masterpiece of art that I had envisioned in my mind but rather with a burning spark of passion, ready to ignite.
Ahn Vo (UC Davis)
With college selectivity increasing and acceptance rates plummeting, the competitive nature within every student is pushed to the limit. In high school, students are expected to pad up their resumes and most importantly, choose an academic path sooner rather than later. However, at 15, I felt too young to experience true passion for a field. As I tried to envision myself in the future, I wondered, would I be someone with the adrenaline and spirit of someone who wants to change the world or one with hollow ambitions, merely clinging onto a paycheck with each day passing? At the very least, I knew that I didn’t want to be the latter.
The unrelenting anxiety induced by the uncertainty of my own ambitions was intoxicating. As my high school career reached its halfway mark, I felt the caving pressure of having to choose an academic path.
“What do you want to be?” was one of the first questions that my mentor, Whitney Cary, asked me. When I didn’t have an answer, she assured me that I needed to keep my doors open, and the SPARK program was the necessary first step that I needed to take to discovering my passion.
As I reflected on my experience, the SPARK program was undoubtedly the “first step”. It was the first step into a lab and above all, into a community of scientists, who share a passion for research and a vehement resolve to contribute to scientific merit. It was the integration into a cohort of other high school students, whose brilliance and kindness allowed us to forge deeper bonds with each other that we will hold onto, even as we part ways. It was the first nervous step into the bay where I met the Stem Cell Core, a team, whose warm laughter and vibrancy felt contagious. Finally, it was the first uncertain stumble into the tissue culture room, where I conceived a curiosity for cell culture that made me never stop asking, “Why?”
With boundless patience, my mentor and the Stem Cell Core strove to teach me techniques, such as immunocytochemistry and continually took the time out of their busy day to reiterate concepts. Despite my initial blunders in the hood, I found myself in a place without judgement, and even after discouraging incidents, I felt a sense of consolation in the witty and good-humored banter among the Stem Cell Core. At the end of every day, the unerring encouragement from my mentor strengthened my resolve to continue improving and incited an earnest excitement in me for the new day ahead. From trembling hands, nearly tipping over culture plates and slippery gloves, overdoused in ethanol, I eventually became acquainted with daily cell culture, and most importantly, I gained confidence and pride in my work.
I am grateful to CIRM for granting me this experience that has ultimately cultivated my enthusiasm for science and for the opportunity to work alongside remarkable people, who have given me new perspectives and insights. I am especially thankful to my mentor, whose stories of her career journey have inspired me to face the future with newfound optimism in spite of adversity.
As my internship comes to a close, I know that I have taken my “first step”, and with a revived mental acquisitiveness, I eagerly begin to take my second.
Other 2017 SPARK Awards
Student Speakers: Candler Cusato (Cedars-Sinai), Joshua Ren (Stanford)
Instagram/Social Media: Jazmin Aizpuru (UCSF), Emily Beckman (CHORI), Emma Friedenberg (Cedars-Sinai)
Poster Presentations: Alexander Escudero (Stanford), Jamie Kim (CalTech), Hector Medrano (CalTech), Zina Patel (City of Hope)
The axolotl, a member of the salamander family, has amazing regenerative abilities. You can cut off its limbs or crush its spinal cord and it will repair itself with no scarring. A human’s healing powers, of course, are much more limited.
To get around this unfortunate fact, the field of regenerative medicine aims to develop stem cell-based therapies that provide the body with that extra oomph of regenerative ability to rid itself of disease or injury. But most of the current approaches in development rely on complex and expensive manufacturing processes in clinical labs before the cells can be safely transplanted in a patient’s body. Wouldn’t it be nice if we could just give the cells already in our bodies some sort of spark to allow them to repair other diseased or damaged cells?
A research team at Ohio State University have taken a fascinating step toward that seemingly science fiction scenario. Reporting this week in Nature Nanotechnology, the scientists describe a technique that – with some DNA, a nanochip and an electric current placed on the skin – can help mice regrow blood vessels to restore dying tissue.
The foundation of this technique is cellular reprogramming. Induced pluripotent stem cells are the most well-known example of reprogramming in which adult cells, like skin or blood, are converted, in a lab dish, to an embryonic stem cell-like state by introducing a set of reprogramming genes into the cells. From there, the stem cells can be specialized into any cell type.
Now, you wouldn’t want to convert skin or blood cells inside the body into quasi embryonic stem cells because they could generate tumors due to their limitless ability to multiply. In this study, the researchers rely on a related method, direct reprogramming, that skips the stem cell step and uses a different set of genes to directly convert one cell type into another. They focused on the direct reprogramming, in mice, of skin cells to endothelial cells, a key component of blood vessels, in mice that were given symptoms mimicking those seen in human injury-induced limb ischemia. This condition leads to a risk of gangrene and amputation when severely injured limbs deteriorate due to blocked blood vessels.
It’s one thing to introduce, or transfect, reprogramming genes into cells that are grown in the very controlled environment of a petri dish. But how the heck does one get DNA into skin cells on the leg of a mouse? That’s where the team’s tissue nano-transfection (TNT) approach comes into the picture. After rubbing off a small section of dead skin on the leg, the TNT device, composed of an nanochip electrode and tiny channels of liquid containing reprogramming DNA, is placed on the skin. A short pulse of electricity is applied which opens miniscule holes in the membranes of skin cells that are in contact with the electrode which allows the DNA to enter the cells. Here’s a short video describing the process:
Three weeks after the procedure, blood vessels had formed, blood flow was restored and the legs of the mice were saved. Team leader, Dr. Chandan Sen, described the results in an interview with National Public Radio:
“Not only did we make new cells, but those cells reorganized to make functional blood vessels that plumb with the existing vasculature and carry blood.”
It’s surprising that TNT reprogramming affects more than just the skin cells that were in contact with the device. But it appears the reprogramming instructions from the introduced DNA was somehow spread to other cells through tiny vesicles called exosomes. When Sen’s team extracted those exosomes and introduced them to skin cells in a petri dish, those cells specialized into blood vessel cells.
This result did attract some skepticism from the field. In the NPR story, stem cell expert Dr. Sean Morrison had this to say:
“There are all manners of claims of these vesicles. It’s not clear what these things are, and if it’s a real biological process or if it’s debris.”
Clearly, more work is needed before TNT is ready for clinical trials in humans. But if it holds up, the technique could bring us closer to the incredible self-healing powers of the axolotl.
Laurel Barchas is an old and dear friend of the communications team here at CIRM. As a student at U.C. Berkeley she helped us draft our education portal – putting together a comprehensive curriculum to help high schools teach students about stem cells in a way that met all state and federal standards. But a funny thing happened on her way to her Ph.D., she realized she had changed her mind about research, and so she changed her career direction.
Laurel recently wrote this blog about that experience for the new and improved website of the Student Society for Stem Cell Research (SSSCR) –
Stem cell parental advice—you can grow up to be anything!
I was one of those students who, since high school, knew I was destined for the lab. Throughout some of high school, and all of college and graduate school, I had internships or positions in amazing labs that warmly took me in and trained me how to be a scientist. I loved designing and carrying out experiments on my stem cells, presenting at lab meetings, writing theses, and teaching others about my work through undergraduate lectures and high school presentations. My participation in the Student Society for Stem Cell Research hugely supported all of my efforts; it even enabled me to get one of my first jobs as a contract curriculum writer (a project manager role) with the California Institute for Regenerative Medicine, which launched my writing career.
Four years into my biology PhD program, things became clear that I didn’t want to do research anymore. I couldn’t handle the failure inherent in doing research. I wasn’t able to put in the time and focus necessary to do big experiments—then repeat them over and over. Although I loved science, I wasn’t meant to be a career scientist like many of my colleagues. I was a science communicator. Realizing this, and taking into account my personal struggles, my advisers and I decided the best thing was to get a terminal master’s degree.**
Differentiation—finding the right path
I struggled for a while finding a job that suited me. I worked as an education consultant, writing materials directed at teachers and students. I worked as a marketing, communications and operations assistant for a real estate group. I looked for jobs as a teacher, curriculum developer, and science education program coordinator, but none felt quite right for me. Although I had extensive experience in school developing materials for teachers and giving presentations to students, and I knew education could be a rewarding career path, I wasn’t sure I wanted to be in the academic world anymore.
Finally, I found some listings looking for technical writers. I didn’t even know what that was at the time. Various biotech companies had their feelers out for entry level writers with advanced degrees in biology or STEM fields—and a master’s degree was just fine. It turns out I was a perfect fit. Surprisingly, many people in the “tech com” (technical communications) and “mar com” (marketing communications) departments at my company had a similar experience; they didn’t want careers in research or the medical professions, so they chose communications.
Life as a technical writer—feeling like a glial cell
As a technical writer at my company, I have many responsibilities beyond writing and editing user manuals, application notes, and diagrams. Tech writers are much like the oft-forgotten glial cells that “glue the brain together.” I manage each project from start to finish, and I get to work on all types of technical documentation and marketing collateral with a team of company scientists (R&D), graphic designers, marketing specialists, coders, product managers, and other writers. Often, I have major creative input on the content, design, and development of marketing campaigns. I enjoy starting with ideas—maybe a few bullet points or a rough draft—and building colorful, captivating content. It feels like solving a complex puzzle.
I’ve gotten the chance to write articles on human induced pluripotent stem cell-derived beta cells for a drug discovery publication and to create portals for our website. I’ve helped make booth panels and printed resources for conferences like the International Society for Stem Cell Research. Most importantly (to me), I’ve managed to stay within the field of stem cell research/regenerative medicine. I am the main writer for that product and service line, so I can use my expertise and experience (plus, knowledge of my audience) to present products that advance my audience’s basic, translational and clinical research.
I love my job. It pays well, has regular hours, and gives me a sense of belonging to a team. It’s fast paced, I’m working on a new thing every day, and I get to learn and write about the latest advancements from our R&D teams around the world. I could go on and on, but suffice it to say that the job fits like a glove, and I can see myself doing this long term. Also…I get to live in Silicon Valley! (Pros: great food, culture, people. Cons: cost of living, traffic.)
I hope you can get encouragement from the retelling of my experience that there is a space for you in this field. This is the first post in a series of articles about careers in regenerative medicine. I aim to take you through a tour of the vocational landscape—its ups, its downs—and am looking forward to hearing from you with any jobs/roles/scenarios you are curious about. Please comment on what you’d like to learn about next!
Remember: there are plenty of options and ways for you to apply your talent and experience to pushing our field forward. SSSCR is here to help!
*I want to thank everyone who serves in the research and medical areas. Without you our field would stop in its tracks. However, not everyone is cut out for such positions. Luckily, there are other options.
**Some reading this might say “awwwww, too bad, she was so close to that PhD” and some might say “that’s a major accomplishment and you can do a lot with that degree!” Both are right, but I choose to believe the latter, as I am so much happier now that I released myself from the allure of lab research and went into science communications. We tend to hold science and medicine up on pedestals; however, science communication facilitates almost all interactions between academic and industry scientists, clinicians, and the public. An understanding of and engagement with new science is critical to promoting a healthy democracy with citizens who can make informed decisions about their society’s future.
Laurel is a co-founder of SSSCR, the current Associate Director, and a member of the SSSCR International executive committee. She has been involved in SSSCR since 2004, when she helped start UC Berkeley’s chapter. Her main contributions are educating various communities about stem cell research and building career development opportunities for students. Along with a team of SSSCR members, Laurel created the California Institute for Regenerative Medicine’s stem cell education portal to provide teachers with the materials they need to engage students with the field. Currently, Laurel is a Senior Technical Writer focused on stem cell products and services.
This may be the first time that the Australian pop group the Bee Gees have ever been featured in a blog about stem cell research, but in this case I think it’s appropriate. One of the Bee Gees biggest hits was “How can you mend a broken heart” and while it was a fine song, Barry and Robin Gibb (who wrote the song) never really came up with a viable answer.
Happily some researchers at the University of Southern California may succeed where Barry and Robin failed. In a study, published in the journal Nature Genetics, the USC team identify a gene that may help regenerate damaged heart tissue after a heart attack.
When babies are born they have a lot of a heart muscle cell called a mononuclear diploid cardiomyocyte or MNDCM for short. This cell type has powerful regenerative properties and so is able to rebuild heart muscle. However, as we get older we have less and less MNDCMs. By the time most of us are at an age where we are most likely to have a heart attack we are also most likely to have very few of these cells, and so have a limited ability to repair the damage.
Michaela Patterson, and her colleagues at USC, set out to find ways to change that. They found that in some adult mice less than 2 percent of their heart cells were MNDCMs, while other mice had a much higher percentage, around 10 percent. Not surprisingly the mice with the higher percentage of MNDCMs were better able to regenerate heart muscle after a heart attack or other injury.
So the USC team – with a little help from CIRM funding – dug a little deeper and did a genome-wide association study of these mice, that’s where they look at all the genetic variants in different individuals to see if they can spot common traits. They found one gene, Tnni3k, that seems to play a key role in generating MNDCMs.
Turning Tnni3K off in mice resulted in higher numbers of MNDCMs, increasing their ability to regenerate heart muscle. But when they activated Tnni3k in zebrafish it reduced the number of MNDCMs and impaired the fish’s ability to repair heart damage.
While it’s a long way from identifying something interesting in mice and zebrafish to seeing if it can be used to help people, Henry Sucov, the senior author on the study, says these findings represent an important first step in that direction:
“The activity of this gene, Tnni3k, can be modulated by small molecules, which could be developed into prescription drugs in the future. These small molecules could change the composition of the heart over time to contain more of these regenerative cells. This could improve the potential for regeneration in adult hearts, as a preventative strategy for those who may be at risk for heart failure.”
Stem cell stories that caught our eye: skin grafts fight diabetes, reprogramming the immune system, and Asterias expands spinal cord injury trial sites
Here are the stem cell stories that caught our eye this week.
Skin grafts fight diabetes and obesity.
An interesting new gene therapy strategy for fighting type 1 diabetes and obesity surfaced this week. Scientists from the University of Chicago made genetically engineered skin grafts that secrete a peptide hormone called glucagon-liked peptide-1 (GLP-1). This peptide is released by cells in the intestine and can lower blood sugar levels by stimulating pancreatic islet cells to secrete insulin (a hormone that promotes the absorption of glucose from the blood).
The study, which was published in the journal Cell Stem Cell, used CRISPR gene editing technology to introduce a mutation to the GLP-1 gene in mouse and human skin stem cells. This mutation stabilized the GLP-1 peptide, allowing it to hang around in the blood for longer. The team matured these stem cells into skin grafts that secreted the GLP-1 into the bloodstream of mice when treated with a drug called doxycycline.
On a normal diet, mice that received the skin graft saw a rise in their insulin levels and a decrease in their blood glucose levels, proving that the gene therapy was working. On a high fat diet, mice with the skin graft became obese, but when they were treated with doxycycline, GLP-1 secreted from their grafts reduced the amount of weight gain. So not only does their engineered skin graft technology look like a promising new strategy to treat type 1 diabetes patients, it also could be used to control obesity. The beauty of the technology is in its simplicity.
An article in Genetic Engineering and Biotechnology News that covered this research explained that Xiaoyang Wu, the senior author on the study, and his team “worked with skin because it is a large organ and easily accessible. The cells multiply quickly and are easily transplanted. And, transplanted cells can be removed, if needed. “Skin is such a beautiful system,” Wu says, noting that its features make it a perfect medium for testing gene therapies.”
Wu concluded that, “This kind of therapy could be potentially effective for many metabolic disorders.” According to GenBio, Wu’s team “is now testing the gene-therapy technique in combination with other medications.” They also hope that a similar strategy could be used to treat patients that can’t make certain proteins like in the blood clotting disorder hemophilia.
How to reprogram your immune system (Kevin McCormack)
When your immune system goes wrong it can cause all manner of problems, from type 1 diabetes to multiple sclerosis and cancer. That’s because an overactive immune system causes the body to attack its own tissues, while an underactive one leaves the body vulnerable to outside threats such as viruses. That’s why scientists have long sought ways to correct those immune dysfunctions.
Now researchers at the Gladstone Institutes in San Francisco think they have found a way to reprogram specific cells in the immune system and restore a sense of health and balance to the body. Their findings are published in the journal Nature.
The researchers identified a drug that targets effector T cells, which get our immune system to defend us against outside threats, and turns them into regulatory T cells, which control our immune system and stops it from attacking our own body.
Why would turning one kind of T cell into another be helpful? Well, in some autoimmune diseases, the effector T cells become overly active and attack healthy tissues and organs, damaging and even destroying them. By converting them to regulatory T cells you can prevent that happening.
In addition, some cancers can hijack regulatory T cells and suppress the immune system, allowing the disease to spread. By turning those cells into effector T cells, you can boost the immune system and give it the strength to fight back and, hopefully, kill the cancer.
In a news release, Gladstone Senior Investigator Sheng Ding, the lead scientists on the study, said their findings could have several applications:
“Our findings could have a significant impact on the treatment of autoimmune diseases, as well as on stem cell and immuno-oncology therapies.”
CIRM-funded spinal cord injury trial expands clinical sites
We have another update from CIRM’s clinical trial front. Asterias Biotherapeutics, which is testing a stem cell treatment for complete cervical (neck) spinal cord injury, is expanding its clinical sites for its CIRM-funded SCiStar Phase 1/2a trial. The company is currently treating patients at six sites in the US, and will be expanding to include two additional sites at Thomas Jefferson University Hospital in Philadelphia and the UC San Diego Medical Center, which is part of the UCSD Health CIRM Alpha Stem Cell Clinic.
In a company news release, Ed Wirth, Chief Medical Officer of Asterias said,
“We are excited about the clinical site openings at Thomas Jefferson University Hospital and UC San Diego Health. These sites provide additional geographical reach and previous experience with spinal cord injury trials to our SCiStar study. We have recently reported completion of enrollment in four out of five cohorts in our SCiStar study so we hope these institutions will also participate in a future, larger study of AST-OPC1.”
The news release also gave a recap of the trial’s positive (but still preliminary) results this year and their plans for completing trial enrollment.
“In June 2017, Asterias reported 9 month data from the AIS-A 10 million cell cohort that showed improvements in arm, hand and finger function observed at 3-months and 6-months following administration of AST-OPC1 were confirmed and in some patients further increased at 9-months. The company intends to complete enrollment of the entire SCiStar study later this year, with multiple safety and efficacy readouts anticipated during the remainder of 2017 and 2018.”
Last week the scientific community was buzzing with the news that US scientists had genetically modified human embryos using CRISPR gene editing technology. While the story broke before the research was published, many journalists and news outlets weighed in on the study’s findings and the ethical implications they raise. We covered this initial burst of news in last week’s stem cell stories that caught our eye.
After a week of suspense, the highly-anticipated study was published yesterday in the journal Nature. The work was led by senior author Dr. Shoukhrat Mitalipov from Oregon Health and Sciences University (and a member of CIRM’s Grants Working Group, the panel of experts who review applications to us for funding) in collaboration with scientists from the Salk Institute and Korea’s Institute for Basic Science.
In brief, the study revealed that the teams’ CRISPR technology could correct a genetic mutation that causes a disease called hypertrophic cardiomyopathy (HCM) in 72% of human embryos without causing off-target effects, which are unwanted genome modifications caused by CRISPR. These findings are a big improvement over previous studies by other groups that had issues with off-target effects and mosaicism, where CRISPR only correctly modifies mutations in some but not all cells in an embryo.
Mitalipov spoke to STATnews about a particularly interesting discovery that he and the other scientists made in the Nature study,
“The main finding is that the CRISPR’d embryos did not accept the “repair DNA” that the scientists expected them to use as a replacement for the mutated gene deleted by CRISPR, which the embryos inherited from their father. Instead, the embryos used the mother’s version of the gene, called the homologue.”
Sharon Begley, the author of the STATnews article, argued that this discovery means that “designer babies” aren’t just around the corner.
“If embryos resist taking up synthetic DNA after CRISPR has deleted an unwanted gene, then “designer babies,” created by inserting a gene for a desirable trait into an embryo, will likely be more difficult than expected.”
Ed Yong from the Atlantic also took a similar stance towards Mitalipov’s study in his article titled “The Designer Baby Era is Not Upon Us”. He wrote,
“The bigger worry is that gene-editing could be used to make people stronger, smarter, or taller, paving the way for a new eugenics, and widening the already substantial gaps between the wealthy and poor. But many geneticists believe that such a future is fundamentally unlikely because complex traits like height and intelligence are the work of hundreds or thousands of genes, each of which have a tiny effect. The prospect of editing them all is implausible. And since genes are so thoroughly interconnected, it may be impossible to edit one particular trait without also affecting many others.”
Dr. Juan Carlos Izpisua Belmonte, who’s a corresponding author on the paper and a former CIRM grantee from the Salk Institute, commented on the impact that this research could have on human health in a Salk news release.
“Thanks to advances in stem cell technologies and gene editing, we are finally starting to address disease-causing mutations that impact potentially millions of people. Gene editing is still in its infancy so even though this preliminary effort was found to be safe and effective, it is crucial that we continue to proceed with the utmost caution, paying the highest attention to ethical considerations.”
Pam Belluck from The New York Times also suggested that this research could have a significant impact on how we prevent disease in newborns.
“This research marks a major milestone and, while a long way from clinical use, it raises the prospect that gene editing may one day protect babies from a variety of hereditary conditions.”
So when will the dawn of CRISPR babies arrive? Ed Yong took a stab at answering this million dollar question with help from experts in the field.
“Not for a while. The technique would need to be refined, tested on non-human primates, and shown to be safe. “The safety studies would likely take 10 to 15 years before FDA or other regulators would even consider allowing clinical trials,” wrote bioethicist Hank Greely in a piece for Scientific American. “The Mitalipov research could mean that moment is 9 years and 10 months away instead of 10 years, but it is not close.” In the meantime, Mitalipov’s colleague Sanjiv Kaul says, “We’ll get the method to perfection so that when it’s possible to use it in a clinical trial, we can.”