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CIRM Stem Cell Blog
Newest member of CIRM Board is a fan of horses, Star Trek and Harry Potter – oh, and she just happens to be a brilliant cancer researcher too.
An addition to the family is always a cause for celebration, whether it be a new baby, a puppy, or, in our case, a new Board member. That’s why we are delighted to welcome City of Hope’s Linda Malkas, Ph.D., as the newest member of the CIRM Board.
Dr. Malkas has a number of titles including Professor of Molecular and Cellular Biology at Beckman Research Institute; Deputy Director of Basic Research, Comprehensive Cancer Center, City of Hope; and joint head of the Molecular Oncology Program at the Cancer Center.
Her research focus is cancer and she has a pretty impressive track record in the areas of human cell DNA replication/repair, cancer cell biomarker and therapeutic target discovery. As evidence of that, she discovered a molecule that can inhibit certain activities in cancerous cells and hopes to move that into clinical trials in the near future.
California Treasure John Chiang made the appointment saying Dr. Malkas is “extraordinarily well qualified” for the role. It’s hard to disagree. She has a pretty impressive resume:
- She served for five years on a National Cancer Institute (NCI) subcommittee reviewing cancer center designations.
- She has served as chair on several NCI study panels and recently took on an advisory role on drug approval policy with the Food and Drug Administration.
- She has published more than 75 peer-reviewed articles
- She sits on the editorial boards of several high profile medical journals.
In a news release Dr. Malkas says she’s honored to be chosen to be on the Board:
“The research and technologies developed through this agency has benefited the health of not only Californians but the nation and world itself. I am excited to see what the future holds for the work of this agency.”
With all this in her work life it’s hard to imagine she has time for a life outside of the lab, and yet she does. She has four horses that she loves to ride – not all at the same time we hope – a family, friends, dogs and cats she likes spending time with. And as if that wasn’t enough to make you want to get to know her, she’s a huge fan of Star Trek, vintage sci-fi movies and Harry Potter.
As part of our CIRM scholar blog series, we’re featuring the research and career accomplishments of CIRM funded students.
Shannon Larsuel is a high school senior at Mayfield Senior School in Pasadena California. Last summer, she participated in Stanford’s CIRM SPARK high school internship program and did stem cell research in a lab that studies leukemia, a type of blood cancer. Shannon is passionate about helping people through research and medicine and wants to become a pediatric oncologist. She is also dedicated to inspiring young girls to pursue STEM (Science, Technology, Engineering, and Mathematics) careers through a group called the Stem Sisterhood.
I spoke with Shannon to learn more about her involvement in the Stem Sisterhood and her experience in the CIRM SPARK program. Her interview is below.
Q: What is the Stem Sisterhood and how did you get involved?
SL: The Stem Sisterhood is a blog. But for me, it’s more than a blog. It’s a collective of women and scientists that are working to inspire other young scientists who are girls to get involved in the STEM field. I think it’s a wonderful idea because girls are underrepresented in STEM fields, and I think that this needs to change.
I got involved in the Stem Sisterhood because my friend Bridget Garrity is the founder. This past summer when I was at Stanford, I saw that she was doing research at Caltech. I reconnected with her and we started talking about our summer experiences working in labs. Then she asked me if I wanted to be involved in the Stem Sisterhood and be one of the faces on her website. She took an archival photo of Albert Einstein with a group of other scientists that’s on display at Caltech and recreated it with a bunch of young women who were involved in the STEM field. So I said yes to being in the photo, and I’m also in the midst of writing a blog post about my experience at Stanford in the SPARK program.
Q: What does the Stem Sisterhood do?
SL: Members of the team go to elementary schools and girl scout troop events and speak about science and STEM to the young girls. The goal is to inspire them to become interested in science and to teach them about different aspects of science that maybe are not that well known.
The Stem Sisterhood is based in Los Angeles. The founder Bridget wants to expand the group, but so far, she has only done local events because she is a senior in high school. The Stem Sisterhood has an Instagram account in addition to their blog. The blog is really interesting and features interviews with women who are in science and STEM careers.
Q: How has the Stem Sisterhood impacted your life?
SL: It has inspired me to reach out to younger girls more about science. It’s something that I am passionate about, and I’d like to pursue a career in the medical field. This group has given me an outlet to share that passion with others and to hopefully change the face of the STEM world.
Q: How did you find out about the CIRM SPARK program?
SL: I knew I wanted to do a science program over the summer, but I wasn’t sure what type. I didn’t know if I wanted to do research or be in a hospital. I googled science programs for high school seniors, and I saw the one at Stanford University. It looked interesting and Stanford is obviously a great institution. Coming from LA, I was nervous that I wouldn’t be able to get in because the program had said it was mostly directed towards students living in the Bay Area. But I got in and I was thrilled. So that’s basically how I heard about it, because I googled and found it.
Q: What was your SPARK experience like?
SL: My program was incredible. I was a little bit nervous and scared going into it because I was the only high school student in my lab. As a high school junior going into senior year, I was worried about being the youngest, and I knew the least about the material that everyone in the lab was researching. But my fears were quickly put aside when I got to the lab. Everyone was kind and helpful, and they were always willing to answer my questions. Overall it was really amazing to have my first lab experience be at Stanford doing research that’s going to potentially change the world.
I was in a lab that was using stem cells to characterize a type of leukemia. The lab is hoping to study leukemia in vitro and in vivo and potentially create different treatments and cures from this research. It was so cool knowing that I was doing research that was potentially helping to save lives. I also learned how to work with stem cells which was really exciting. Stem cells are a new advancement in the science world, so being able to work with them was incredible to me. So many students will never have that opportunity, and being only 17 at the time, it was amazing that I was working with actual stem cells.
I also liked that the Stanford SPARK program allowed me to see other aspects of the medical world. We did outreach programs in the Stanford community and helped out at the blood drive where we recruited people for the bone marrow registry. I never really knew anything about the registry, but after learning about it, it really interested me. I actually signed up for it when I turned 18. We also met with patients and their families and heard their stories about how stem cell transplants changed their lives. That was so inspiring to me.
Going into the program, I was pretty sure I wanted to be a pediatric oncologist, but after the program, I knew for sure that’s what I wanted to do. I never thought about the research side of pediatric oncology, I only thought about the treatment of patients. So the SPARK program showed me what laboratory research is like, and now that’s something I want to incorporate into my career as a pediatric oncologist.
I learned so much in such a short time period. Through SPARK, I was also able to connect with so many incredible, inspired young people. The students in my program and I still have a group chat, and we text each other about college and what’s new with our lives. It’s nice knowing that there are so many great people out there who share my interests and who are going to change the world.
Q: What was your favorite part of the SPARK program?
SL: Being in the lab every day was really incredible to me. It was my first research experience and I was in charge of a semi-independent project where I would do bacterial transformations on my own and run the gels. It was cool that I could do these experiments on my own. I also really loved the end of the summer poster session where all the students from the different SPARK programs came together to present their research. Being in the Stanford program, I only knew the Stanford students, but there were so many other awesome projects that the other SPARK students were doing. I really enjoyed being able to connect with those students as well and learn about their projects.
Q: Why do you want to pursue pediatric oncology?
SL: I’ve always been interested in the medical field but I’ve had a couple of experiences that really inspired me to become a doctor. My friend has a charity that raises money for Children’s Hospital Los Angeles. Every year, we deliver toys to the hospital. The first year I participated, we went to the hospital’s oncology unit and something about it stuck with me. There was one little boy who was getting his chemotherapy treatment. He was probably two years old and he really inspired to create more effective treatments for him and other children.
I also participated in the STEAM Inquiry program at my high school, where I spent two years reading tons of peer reviewed research on immunotherapy for pediatric cancer. Immunotherapy is something that really interests me. It makes sense that since cancer is usually caused by your body’s own mutations, we should be able to use the body’s immune system that normally regulates this to try and cure cancer. This program really inspired me to go into this field to learn more about how we can really tailor the immune system to fight cancer.
Q: What advice do you have for young girls interested in STEM.
SL: My advice is don’t be afraid. I think that sometimes girls are expected to be interested in less intellectual careers. This perception can strike fear into girls and make them think “I won’t be good enough. I’m not smart enough for this.” This kind of thinking is not good at all. So I would say don’t be afraid and be willing to put yourself out there. I know for me, sometimes it’s scary to try something and know you could fail. But that’s the best way to learn. Girls need to know that they are capable of doing anything and if they just try, they will be surprised with what they can do.
Everything we do at CIRM is laser-focused on our mission: to accelerate stem cell treatments for patients with unmet medical needs. So, you might imagine what a thrill it is to meet the people who could be helped by the stem cell research we fund. People like Rosie Barrero who suffers from Retinitis Pigmentosa (RP), an inherited, incurable form of blindness, which she describes as “an impressionist painting in a foggy room”.
The CIRM team first met Rosie Barrero back in 2012 at one of our governing Board meetings. She and her husband, German, attended the meeting to advocate for a research grant application submitted by UC Irvine’s Henry Klassen. The research project aimed to bring a stem cell-based therapy for RP to clinical trials. The Board approved the project giving a glimmer of hope to Rosie and many others stricken with RP.
Now, that hope has become a reality in the form of a Food and Drug Administration (FDA)-approved clinical trial which Rosie participated in last year. Sponsored by jCyte, a company Klassen founded, the CIRM-funded trial is testing the safety and effectiveness of a non-surgical treatment for RP that involves injecting stem cells into the eye to help save or even restore the light-sensing cells in the back of the eye. The small trial has shown no negative side effects and a larger, follow-up trial, also funded by CIRM, is now recruiting patients.
Almost five years after her first visit, Rosie returned to the governing Board in February and sprinkled in some of her witty humor to describe her preliminary yet encouraging results.
“It has made a difference. I’m still afraid of public speaking but early on [before the clinical trial] it was much easier because I couldn’t see any of you. But, hello everybody! I can see you guys. I can see this room. I can see a lot of things.”
After the meeting, she sat down for an interview with the Stem Cellar team to talk about her RP story and her experience as a clinical trial participant. The three-minute video above is based on that interview. Watch it and be inspired!
Three letters, C-A-G, can make the difference between being healthy and having a genetic brain disorder called Huntington’s disease (HD). HD is a progressive neurodegenerative disease that affects movement, cognition and personality. Currently more than 30,000 Americans have HD and there is no cure or treatment to stop the disease from progressing.
A genetic mutation in the huntingtin gene. caused by an expanded repeat of CAG nucleotides, the building blocks of DNA that make our genes, is responsible for causing HD. Normal people have less than 26 CAG repeats while those with 40 or more repeats will get HD. The reasons are still unknown why this trinucleotide expansion causes the disease, but scientists hypothesize that the extra CAG copies in the huntingtin gene produce a mutant version of the Huntingtin protein, one that doesn’t function the way the normal protein should.
As with many diseases, things start to go wrong in the body long before symptoms of the disease reveal themselves. This is the case for HD, where symptoms typically manifest in patients between the ages of 30 and 50 but problems at the molecular and cellular level occur decades before. Because of this, scientists are generating new models of HD to unravel the mechanisms that cause this disease early on in development.
Induced pluripotent stem cells (iPSCs) derived from HD patients with expanded CAG repeats are an example of a cell-based model that scientists are using to understand how HD affects brain development. In a CIRM-funded study published today in the journal Nature Neuroscience, scientists from the HD iPSC Consortium used HD iPSCs to study how the HD mutation causes problems with neurodevelopment.
They analyzed neural cells made from HD patient iPSCs and looked at what genes displayed abnormal activity compared to healthy neural cells. Using a technique called RNA-seq analysis, they found that many of these “altered” genes in HD cells played important roles in the development and maturation of neurons, the nerve cells in the brain. They also observed differences in the structure of HD neurons compared to healthy neurons when grown in a lab. These findings suggest that HD patients likely have problems with neurodevelopment and adult neurogenesis, the process where the adult stem cells in your brain generate new neurons and other brain cells.
After pinpointing the gene networks that were altered in HD neurons, they identified a small molecule drug called isoxazole-9 (Isx-9) that specifically targets these networks and rescues some of the HD-related symptoms they observed in these neurons. They also tested Isx-9 in a mouse model of HD and found that the drug improved their cognition and other symptoms related to impaired neurogenesis.
The authors conclude from their findings that the HD mutation disrupts gene networks that affect neurodevelopment and neurogenesis. These networks can be targeted by Isx-9, which rescues HD symptoms and improves the mental capacity of HD mice, suggesting that future treatments for HD should focus on targeting these early stage events.
I reached out to the leading authors of this study to gain more insights into their work. Below is a short interview with Dr. Leslie Thompson from UC Irvine, Dr. Clive Svendsen from Cedars-Sinai, and Dr. Steven Finkbeiner from the Gladstone Institutes. The responses were mutually contributed.
Q: What is the mission of the HD iPSC Consortium?
To create a resource for the HD community of HD derived stem cell lines as well as tackling problems that would be difficult to do by any lab on its own. Through the diverse expertise represented by the consortium members, we have been able to carry out deep and broad analyses of HD-associated phenotypes [observable characteristics derived from your genome]. The authorship of the paper – the HD iPSC consortium (and of the previous consortium paper in 2012) – reflects this goal of enabling a consortium and giving recognition to the individuals who are part of it.
Q: What is the significance of the findings in your study and what novel insights does it bring to the HD field?
Our data revealed a surprising neurodevelopmental effect of highly expanded repeats on the HD neural cells. A third of the changes reflected changes in networks that regulate development and maturation of neurons and when compared to neurodevelopment pathways in mice, showed that maturation appeared to be impacted. We think that the significance is that there may be very early changes in HD brain that may contribute to later vulnerability of the brain due to the HD mutation. This is compounded by the inability to mount normal adult neurogenesis or formation of new neurons which could compensate for the effects of mutant HTT. The genetic mutation is present from birth and with differentiated iPSCs, we are picking up signals earlier than we expected that may reflect alterations that create increased susceptibility or limited homeostatic reserves, so with the passage of time, symptoms do result.
What we find encouraging is that using a small molecule that targets the pathways that came out of the analysis, we protected against the impact of the HD mutation, even after differentiation of the cells or in an adult mouse that had had the mutation present throughout its development.
Q: There’s a lot of evidence suggesting defects in neurodevelopment and neurogenesis cause HD. How does your study add to this idea?
Agree completely that there are a number of cell, mouse and human studies that suggest that there are problems with neurodevelopment and neurogenesis in HD. Our study adds to this by defining some of the specific networks that may be regulating these effects so that drugs can be developed around them. Isx9, which was used to target these pathways specifically, shows that even with these early changes, one can potentially alleviate the effects. In many of the assays, the cells were already through the early neurodevelopmental stages and therefore would have the deficits present. But they could still be rescued.
Q: Has Isx-9 been used previously in cell or animal models of HD or other neurodegenerative diseases? Could it help HD patients who already are symptomatic?
The compound has not been used that we know of in animal models to treat neurodegeneration, although was shown to affect neurogenesis and memory in mice. Isx9 was used in a study by Stuart Lipton in Parkinson’s iPSC-derived neurons in one study and it had a protective effect on apoptosis [cell death] in a study by Ryan SD et al., 2013, Cell.
We think this type of compound could help patients who are symptomatic. Isx-9 itself is a fairly pleiotropic drug [having multiple effects] and more research would be needed [to test its safety and efficacy].
Q: Have you treated HD mice with Isx-9 during early development to see whether the molecule improves HD symptoms?
Not yet, but we would like to.
Q: What are your next steps following this study and do you have plans to translate this research into humans?
We are following up on the research in more mature HD neurons and to determine at what stages one can rescue the HD phenotypes in mice. Also, we would need to do pharmacodynamics and other types of assays in preclinical models to assess efficacy and then could envision going into human trials with a better characterized drug. Our goal is to ultimately translate this to human treatments in general and specifically by targeting these altered pathways.
Stem Cell Stories that Caught our Eye: stem cell insights into anorexia, Zika infection and bubble baby disease
Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.
Stem cell model identifies new culprit for anorexia.
Eating disorders like anorexia nervosa are often thought to be caused by psychological disturbances or societal pressure. However, research into the genes of anorexia patients suggests that what’s written in your DNA can be associated with an increased vulnerability to having this disorder. But identifying individual genes at fault for a disease this complex has remained mostly out of scientists’ reach, until now.
A CIRM-funded team from the UC San Diego (UCSD) School of Medicine reported this week that they’ve developed a stem cell-based model of anorexia and used it to identify a gene called TACR1, which they believe is associated with an increased likelihood of getting anorexia.
They took skin samples from female patients with anorexia and reprogrammed them into induced pluripotent stem cells (iPSCs). These stem cells contained the genetic information potentially responsible for causing their anorexia. The team matured these iPSCs into brain cells, called neurons, in a dish, and then studied what genes got activated. When they looked at the genes activated by anorexia neurons, they found that TACR1, a gene associated with psychiatric disorders, was switched on higher in anorexia neurons than in healthy neurons. These findings suggest that the TACR1 gene could be an identifier for this disease and a potential target for developing new treatments.
In a UCSD press release, Professor and author on the study, Alysson Muotri, said that they will follow up on their findings by studying stem cell lines derived from a larger group of patients.
“But more to the point, this work helps make that possible. It’s a novel technological advance in the field of eating disorders, which impacts millions of people. These findings transform our ability to study how genetic variations alter brain molecular pathways and cellular networks to change risk of anorexia nervosa — and perhaps our ability to create new therapies.”
Anorexia is a disease that affects 1% of the global population and although therapy can be an effective treatment for some, many do not make a full recovery. Stem cell-based models could prove to be a new method for unlocking new clues into what causes anorexia and what can cure it.
Nature versus Zika, who will win?
Zika virus is no longer dominating the news headlines these days compared to 2015 when large outbreaks of the virus in the Southern hemisphere came to a head. However, the threat of Zika-induced birth defects, like microcephaly to pregnant women and their unborn children is no less real or serious two years later. There are still no effective vaccines or antiviral drugs that prevent Zika infection but scientists are working fast to meet this unmet need.
Speaking of which, scientists at UCLA think they might have a new weapon in the war against Zika. Back in 2013, they reported that a natural compound in the body called 25HC was effective at attacking viruses and prevented human cells from being infected by viruses like HIV, Ebola and Hepatitis C.
When the Zika outbreak hit, they thought that this compound could potentially be effective at preventing Zika infection as well. In their new study published in the journal Immunity, they tested a synthetic version of 25HC in animal and primate models, they found that it protected against infection. They also tested the compound on human brain organoids, or mini brains in a dish made from pluripotent stem cells. Brain organoids are typically susceptible to Zika infection, which causes substantial cell damage, but this was prevented by treatment with 25HC.
A UCLA news release summarized the impact that this research could have on the prevention of Zika infection,
“The new research highlights the potential use of 25HC to combat Zika virus infection and prevent its devastating outcomes, such as microcephaly. The research team will further study whether 25HC can be modified to be even more effective against Zika and other mosquito-borne viruses.”
Harnessing a naturally made weapon already found in the human body to fight Zika could be an alternative strategy to preventing Zika infection.
Gene therapy in stem cells gives hope to bubble-babies.
Last week, an inspiring and touching story was reported by Erin Allday in the San Francisco Chronicle. She featured Ja’Ceon Golden, a young baby not even 6 months old, who was born into a life of isolation because he lacked a properly functioning immune system. Ja’Ceon had a rare disease called severe combined immunodeficiency (SCID), also known as bubble-baby disease.
Babies with SCID lack the body’s immune defenses against infectious diseases and are forced to live in a sterile environment. Without early treatment, SCID babies often die within one year due to recurring infections. Bone marrow transplantation is the most common treatment for SCID, but it’s only effective if the patient has a donor that is a perfect genetic match, which is only possible for about one out of five babies with this disease.
Advances in gene therapy are giving SCID babies like Ja’Ceon hope for safer, more effective cures. The SF Chronicle piece highlights two CIRM-funded clinical trials for SCID run by UCLA in collaboration with UCSF and St. Jude Children’s Research Hospital. In these trials, scientists isolate the bone marrow stem cells from SCID babies, correct the genetic mutation causing SCID in their stem cells, and then transplant them back into the patient to give them a healthy new immune system.
The initial results from these clinical trials are promising and support other findings that gene therapy could be an effective treatment for certain genetic diseases. CIRM’s Senior Science Officer, Sohel Talib, was quoted in the Chronicle piece saying,
“Gene therapy has been shown to work, the efficacy has been shown. And it’s safe. The confidence has come. Now we have to follow it up.”
Ja’Ceon was the first baby treated at the UCSF Benioff Children’s Hospital and so far, he is responding well to the treatment. His great aunt Dannie Hawkins said that it was initially hard for her to enroll Ja’Ceon in this trial because she was a partial genetic match and had the option of donating her own bone-marrow to help save his life. In the end, she decided that his involvement in the trial would “open the door for other kids” to receive this treatment if it worked.
It’s brave patients and family members like Ja’Ceon and Dannie that make it possible for research to advance from clinical trials into effective treatments for future patients. We at CIRM are eternally grateful for their strength and the sacrifices they make to participate in these trials.
Today we bring you a guest blog from Athena Mari Asklipiadis. She’s the founder of Mixed Marrow, which is an organization dedicated to finding bone marrow and blood cell donors to patients of multiethnic descent. Athena helped produce a 2016 documentary film called Mixed Match that encourages mixed race and minority donors to register as adult donors.
Due to the lack of diversity on the national and world bone marrow donor registries, Mixed Marrow was started in 2009 to increase the numbers of mixed race donors.
Prior to Mixed Marrow starting, other ethnic recruiters like Asians for Miracle Marrow Matches (A3M), based in Los Angeles, CA and Asian American Donor Program (AADP), based in Alameda, CA had been raising awareness in the Asian and minority communities for decades. Closing the racial gap on the registry was something I was very much interested in helping them with so I began my outreach on the most familiar medium I knew—social media.
Because matching relies heavily on similar inherited genetic markers, I was particularly astonished seeing the less than 3% (back in 2009) sliver of the ethnic pie that mixed race donors made up. Caucasians made up for about 70% at the time, with all minorities making up for the difference. The ethnic breakdown made sense when comparing against actual population numbers, but a larger pool of minority donors was definitely something needed especially when multiracial people were being reported as the fastest growing demographic in the US. Odds were just not in the favor of non-white searching patients.
After getting to know a local mixed race searching patient, Krissy Kobata, and hearing of her struggles finding a match, I knew I had to do my best to reach out to fellow multiracial people, most of which were young and likely online. At the time, I was engaged with fellow hapas (half white, half Asian) and mixed people via multiracial community Facebook groups and other internet forums. One common thing I noticed, unlike topics like identity, food and culture– health was definitely not widely talked about. So with that lack of awareness, Mixed Marrow began as a facebook page and later as a website. With the help of organizations like A3M supplying Be The Match testing kits, Mixed Marrow was able to also exist outside of the virtual world by hosting donor recruitment drives at different cultural and college events.
After about a year of advocacy, in 2010, I connected with filmmaker Jeff Chiba Stearns to pitch an idea for a documentary on the patients I worked with. Telling their stories in words and on flyers was not effective enough for me, I felt that more people would be inclined to register as a donor if they got to know the patients as well as I did. Thus, the film Mixed Match was born.
Over the course of the next 6 years, Jeff and I went on a journey across the US to gather not only patient stories, but input from pioneers in stem cell transplantation like Dr. Paul Terasaki and Dr. John E. Wagner. It was so important to share these transplant tales while being as accurate and informed as possible.
Our goal was to educate audiences and present a call-to-action where everyone can learn how they can save a life. Mixed Match not only highlights bone marrow and peripheral blood stem cell (PBSC) donation, but it also shares the possibilities of umbilical cord stem cells.
Mixed Match director, Jeff Chiba Stearns decided a great way to explain stem cell science and matching was through animation. Stearns, with the help of animator, Kaho Yoshida, was able to reach across to non-medical expert audiences and create digestible and engaging imagery to teach what is usually very complex science.
At every screening we also make sure to host a bone marrow registry drive so audiences have the opportunity to sign up. We have partnered with both the US national registry, Be The Match and Canadian Blood Services’ One Match registry.
Nearly 8 years and about 40 cities later, Mixed Marrow has managed to spread advocacy for the need for more mixed race donors all over the US and even other countries like Canada, Japan, Korea and Austria all the while being completely volunteer-run. It is our hope that through social media and film, Mixed Match, we can help share these important stories and save lives.
- Learn more about Mixed Marrow at www.mixedmarrow.org or @mixedmarrow on social media (Twitter and Instagram).
- For more on the documentary Mixed Match and how you can see it, visit www.mixedmatchproject.com or @mixedmatchmovie on social media (Twitter and Instagram).
- Register in the US as a donor by visiting join.bethematch.org/mixedmatch or by checking out our upcoming drives here: www.mixedmatch.org/calendar
The report makes for chilling reading. Three women, all suffering from macular degeneration – the leading cause of vision loss in the US – went to a Florida clinic hoping that a stem cell therapy would save their eyesight. Instead, it caused all three to go blind.
The study, in the latest issue of the New England Journal of Medicine, is a warning to all patients about the dangers of getting unproven, unapproved stem cell therapies.
In this case, the clinic took fat and blood from the patient, put the samples through a centrifuge to concentrate the stem cells, mixed them together and then injected them into the back of the woman’s eyes. In each case they injected this mixture into both eyes.
Within days the women, who ranged in age from 72 to 88, began to experience severe side effects including bleeding in the eye, detached retinas, and vision loss. The women got expert treatment at specialist eye centers to try and undo the damage done by the clinic, but it was too late. They are now blind with little hope for regaining their eyesight.
In a news release Thomas Alibini, one of the lead authors of the study, says clinics like this prey on vulnerable people:
“There’s a lot of hope for stem cells, and these types of clinics appeal to patients desperate for care who hope that stem cells are going to be the answer, but in this case these women participated in a clinical enterprise that was off-the-charts dangerous.”
So what went wrong? The researchers say this clinic’s approach raised a number of “red flags”:
- First there is almost no evidence that the fat/blood stem cell combination the clinic used could help repair the photoreceptor cells in the eye that are attacked in macular degeneration.
- The clinic charged the women $5,000 for the procedure. Usually in FDA-approved trials the clinical trial sponsor will cover the cost of the therapy being tested.
- Both eyes were injected at the same time. Most clinical trials would only treat one eye at a time and allow up to 30 days between patients to ensure the approach was safe.
- Even though the treatment was listed on the clinicaltrials.gov website there is no evidence that this was part of a clinical trial, and certainly not one approved by the Food and Drug Administration (FDA) which regulates stem cell therapies.
The study points out that not all projects listed on the Clinicaltrials.gov site are checked to make sure they are scientifically sound and have done the preclinical testing needed to reduce the likelihood they may endanger patients.
Jeffrey Goldberg, a professor of Ophthalmology at Stanford and the co-author of the study, says this is a warning to all patients considering unproven stem cell therapies:
“There is a lot of very well-founded evidence for the positive potential of stem therapy for many human diseases, but there’s no excuse for not designing a trial properly and basing it on preclinical research.”
There are a number of resources available to people considering being part of a clinical trial including CIRM’s “So You Want to Participate in a Clinical Trial” and the website A Closer Look at Stem Cells , which is sponsored by the International Society for Stem Cell Research (ISSCR).
CIRM is currently funding two clinical trials aimed at helping people with vision loss. One is Dr. Mark Humayun’s research on macular degeneration – the same disease these women had – and the other is Dr. Henry Klassen’s research into retinitis pigmentosa. Both these projects have been approved by the FDA showing they have done all the testing required to try and ensure they are safe in people.
In the past this blog has been a vocal critic of the FDA and the lengthy and cumbersome approval process for stem cell clinical trials. We have, and still do, advocate for a more efficient process. But this study is a powerful reminder that we need safeguards to protect patients, that any therapy being tested in people needs to have undergone rigorous testing to reduce the likelihood it may endanger them.
These three women paid $5,000 for their treatment. But the final cost was far greater. We never want to see that happen to anyone ever again.
Everyone loves a good comeback story. Probably because it leaves us feeling inspired and full of hope. But the comeback story about a horse named Dream Alliance may do more than that: his experience promises to help people with Achilles tendon injuries get fully healed and back on their feet more quickly.
Dream Alliance was bred and raised in a very poor Welsh town in the United Kingdom. One of the villagers had the dream of owning a thoroughbred racehorse. She convinced a group of her fellow townsfolk to pitch in $15 dollars a week to cover the costs of training the horse. Despite his lowly origins, Dream Alliance won his fourth race ever and his future looked bright. But during a race in 2008, one of his back hoofs cut a tendon in his front leg. The seemingly career-ending injury was so severe that the horse was nearly euthanized.
It works in horses, how about humans?
Instead, he received a novel stem cell procedure which healed the tendon and, incredibly, the thoroughbred went on to win the Welsh Grand National race 15 months later – one of the biggest races in the UK that is almost 4 miles long and involves jumping 22 fences. Researchers at the Royal Veterinary College in Liverpool developed the method and data gathered from the treatment of 1500 horses with this stem cell therapy show a 50% decrease in re-injury of the tendon.
It’s been so successful in horses that researchers at the University College of London and the Royal National Orthopaedic Hospital are currently running a clinical trial to test the procedure in humans. Over the weekend, the Daily Mail ran a news story about the clinical trial. In it, team lead Andrew Goldberg explained how they got the human trial off the ground:
“Tendon injuries in horses are identical to those in humans, and using this evidence [from the 1500 treated horses] we were able to persuade the regulators to allow us to launch a small safety study in humans.”
Tendon repair: there’s got to be another way
The Achilles tendon is the largest tendon in the body and connects the calf muscle to the heel bone. It takes on a lot of strain during running and jumping so it’s a well-known injury to professional and recreational athletes but injuries also occur in those with a sedentary lifestyle. Altogether Achilles tendon injury occurs in about 5-10 people per 100,000. And about 25%-45% of those injuries require surgery which involves many months of crutches and it doesn’t always work. That’s why this stem cell approach is sorely needed.
The procedure is pretty straight forward as far as stem cell therapies go. Bone marrow from the patient’s hip is collected and mesenchymal stem cells – making up a small fraction of the marrow – are isolated. The stem cells are transferred to petri dishes and allowed to divide until there are several million cells. Then they are injected directly into the injured tendon.
A reason to be cautiously optimistic
Early results from the clinical trial are encouraging with a couple of the patients experiencing improvements. The Daily Mail article featured the clinical trial’s first patient who went from a very active lifestyle to one of excruciating ankle pain due to a gradually deteriorating Achilles tendon. Though hesitant when she first learned about the trial, the 46-year-old ultimately figured that the benefits outweighed the risk. That turned out to be a good decision:
“I worried, because no one had ever had it before, except a horse. But I was more worried I’d end up in a wheelchair. The difference now is amazing. I can do five miles on the treadmill without pain, and take my dog Honey on long walks again.”
The researchers aren’t exactly sure how the therapy works but mesenchymal stem cells are known to release factors that promote regeneration and reduce inflammation. The first patient’s positive results are just anecdotal at this point. The clinical trial is still recruiting volunteers so definitive results are still on the horizon. And even if that small trial is successful, larger clinical trials will be required to confirm effectiveness and safety. It will take time but without the careful gathering of this data, doctors and patients will remain in the dark about their chances for success with this stem cell treatment.
Hopefully the treatment proves to be successful and ushers in a golden era of comeback stories. Not just for star athletes eager to get back on the field but also for the average person whose career, good health and quality of life depends on their mobility.
This blog originally appeared on RegMedNet and was provided by Freya Leask, Editor & Community Manager of RegMedNet. In this interview, Stephen Lin, Senior Science Officer at the California Institute Regenerative Medicine (CIRM), discusses the scope, challenges and potential of CIRM’s iPSC Initiative.
Stephen Lin received his PhD from Washington University (MO, USA) and completed his postdoctoral work at Harvard University (MA, USA). Lin is a senior science officer at CIRM which he joined in 2015 to oversee the development of a $32 million repository of iPSCs generated from up to 3000 healthy and diseased individuals and covering both complex and rare diseases. He also oversees a $40 million initiative to apply genomics and bioinformatics approaches to stem cell research and development of therapies. Lin is the program lead on the CIRM Translating Center which focuses on supporting the process development, safety/toxicity studies and manufacturing of stem cell therapy candidates to prepare them for clinical trials. He was previously a scientist at StemCells, Inc (CA, USA) and a staff scientist team lead at Thermo Fisher Scientific (MA, USA).
Q: Please introduce yourself and your institution.
I completed my PhD at Washington University in biochemistry, studying the mechanisms of aging, before doing my postdoc at Harvard, investigating programmed cell death. After that, I went into industry and have been working with stem cells ever since.
I was at the biotech company StemCells, Inc for 6 years where I worked on cell therapeutics. I then joined what was Life Technologies which is now Thermo Fisher Scientific. I joined CIRM in 2015 as they were launching two new initiatives, the iPSC repository and the genomics initiative, which were a natural combination of my experience in both the stem cells industry and in genetic analysis. I’ve been here for a year and a half, overseeing both initiatives as well as the CIRM Translating Center.
Q: What prompted the development of the iPSC repository?
Making iPSCs is challenging! It isn’t trivial for many research labs to produce these materials, especially for a wide variety of diseases; hence, the iPSC repository was set up in 2013. In its promotion of stem cells, CIRM had the financial resources to develop a bank for researchers and build up a critical mass of lines to save researchers the trouble of recruiting the patients, getting the consents, making and quality controlling the cells. CIRM wanted to cut that out and bring the resources straight to the research community.
Q: What are the challenges of storage so many iPSCs?
Many of the challenges of storing iPSCs and ensuring their quality are overcome with adequate quality controls at the production step. The main challenge is that we’re collecting samples from up to 3000 donors – the logistics of processing that many tissue samples from 11 funded and nonfunded collectors are difficult. The lines are being produced in the same uniform manner by one agency, Cellular Dynamics International (WI, USA), to ensure quality in terms of pluripotency, karyotyping and sterility testing.
Once the lines are made, they are stored at the Coriell Institute (NJ, USA). During storage, there is a challenge in simply keeping track of and distributing that many samples; we will have approximately 40 vials for each of the 3000 main lines. Both Cellular Dynamics and Coriell have sophisticated tracking systems and Coriell have set up a public catalog website where anyone can go to read about and order the lines. Most collections don’t have this functionality, as the IT infrastructure required for searching and displaying the lines along with clinical information, the ordering process, material transfer agreements and, for commercial uses, the licensing agreements was very complex.
Q: Can anyone use the repository?
Yes, they can! There is a fee to utilize the lines but we encourage researchers anywhere in the world to order them. The lines are mostly for research and academic purposes but the collection was built to be commercialized, all the way from collecting the samples. When the samples were collected, the patient consent included, among other things, banking, distribution, genetic characterization and commercialization.
The lines also have pre-negotiated licensing agreements with iPS Academia Japan (Kyoto, Japan) and the Wisconsin Alumni Research Foundation (WI, USA). Commercial entities that want to use the cells for drug screening can obtain a license which allows them to use these lines for drug discovery and drug screening purposes without fear of back payment royalties down the road. People often forget during drug screening that the intellectual property to make the iPSCs is still under patent, so if you do discover a drug using iPSCs without taking care of these licensing agreements, your discovery could be liable to ownership by that original intellectual property holder.
Q: Will wider access to high quality iPSCs accelerate discovery?
That’s our hope. When people make iPSCs, the quality can be highly variable depending on the lab’s background and experience, which was another impetus to create the repository. Cellular Dynamics have set up a very robust system to create these lines in a rigorous quality control pipeline to guarantee that these lines are pluripotent and genetically stable.
Q: What diseases could these lines be used to study and treat?
We collected samples from patients with many different diseases – from neurodevelopmental disorders including epilepsy and neurodegenerative diseases such as Alzheimer’s, to eye disease and diabetes – as well as the corresponding controls. We also have lines from rare diseases, where the communities have no other tools to study them, for example, ADCY5 related dyskinesia. You can read our recent blogs about our efforts to generate new iPSC lines for ADCY5 and other rare diseases here and here.
Q: What are your plans for the iPSC initiative this year?
We’re currently the largest publicly available repository in the world and we aren’t complete yet. We have just under half of the lines in with the other half still being produced and quality controlled. Something else we want to do is add further information to make the lines more valuable and ensure the drug models are constantly improving. The reason people will want to use iPSCs for human disease modeling is whether they have valuable information associated with them. For example, we are trying to add genetic and sequencing information to the catalog for lines that have it. This will also allow researchers to prescreen the lines they are interested in to match the diseases and drugs they are studying.
Q: Does the future for iPSCs lie in being utilized as tools to find therapeutics as opposed to therapeutics themselves?
I think the future is two pronged. There is certainly a future for disease modeling and drug screening. There is currently an initiative within the FDA, the CiPA initiative, is designed to replace current paradigms for drug safety testing with computational model and stem cell models. In particular, they hope to be able to screen drugs for cardiotoxicity in stem cells before they go to patients. Mouse and rodent models have different receptors and ion channels so these cardiotoxic effects aren’t usually seen until clinical trials.
The other avenue is in therapeutics. However, this will come later in the game because the lines being used for research often can’t be used for therapeutics. Patient consent for therapeutic use has to be obtained at sample collection, the tissue should be handled in compliance with good lab practice and the lines must be produced following good manufacturing process (GMP) guidelines. They must then be characterized to ensure they have met all safety protocols for iPSC therapeutics.
There is already a second trial being initiated in Japan of an iPSC therapeutic to treat macular degeneration, utilizing allogenic lines that are human leukocyte antigen-compatible and extensively safety profiled. Companies such as Lonza (Basel, Switzerland) and Cellular Dynamics are starting to produce their own GMP lines, and CIRM is funding some translation programs where clinical grade iPSCs are being produced for therapeutics.
- CIRM Human Pluripotent Stem Cell Repository.
- iPSC Repository: Creating a publically-accessible stem cell repository for disease research and drug discovery.
- McCormack K. The Stem Cell Bank is open for business. The Stem Cellar, September 1, 2015.
- McCormack K. Making a deposit in the Bank: using stem cells from children with rare diseases to find new treatments. The Stem Cellar, September 12, 2016.
- CiPA initiative
Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.
Targeting cancer stem cells. This week, three studies came out with novel ways for targeting cancer stem cells in different types of cancers. Here’s a brief run-down of this trifecta of cancer stem cell-crushing stories:
Take your vitamins! Scientists in the UK were experimenting on cancer stem cells and comparing natural substances to on-the-market cancer drugs to determine whether any of the natural substances were effective at disrupting the metabolism (the chemical reactions that keep cells alive and functioning) of cancer stem cells. Interestingly, they found that ascorbic acid, which you’ll know as Vitamin C, was ten times better at curbing cancer stem cell growth compared to a cancer drug called 2-DG.
Vitamin C has popped up as an anti-cancer treatment in the past when Nobel Laureate Linus Pauling found that it dramatically reduced the death rate in breast cancer patients. However this current study is the first to show that Vitamin C has a direct effect on cancer stem cells.
In coverage by ScienceDaily, the UK team hinted at plans to test Vitamin C in clinical trials:
“Vitamin C is cheap, natural, non-toxic and readily available so to have it as a potential weapon in the fight against cancer would be a significant step. Our results indicate it is a promising agent for clinical trials, and a as an add-on to more conventional therapies, to prevent tumour recurrence, further disease progression and metastasis.”
A gene called ZEB1 determines how aggressive brain tumors are. A team from Cedars-Sinai Medical Center was interested to know how cancer stem cells in aggressive brain tumors called gliomas survive, reproduce and affect patient survival. In a study published in Scientific Reports, they studied the genetic information of over 4000 brain tumor samples and found ZEB1, a gene that regulates tumor growth and is associated with patient survival.
They found that patients with a healthy copy of the ZEB1 gene had a higher survival rate and less aggressive tumors compared to patients that didn’t have ZEB1 or had a mutated version of the gene.
In coverage by ScienceDaily, the senior author on the study explained how their study’s findings will allow for more personalized treatments for patients with glioma based on whether they have ZEB1 or not:
“Patients without the gene in their tumors have more aggressive cancers that act like stem cells by developing into an uncontrollable number of cell types. This new information could help us to measure the mutation in these patients so that we are able to provide a more accurate prognosis and treatment plan.”
Beating resistant tumors by squashing cancer stem cells. Our final cancer stem cell story today comes from the UCLA School of Dentistry. This team is studying another type of aggressive cancer called a squamous cell carcinoma that causes tumors in the head and neck. Often these tumors resist treatment and spread to a patient’s lymph nodes, which quickly reduces their survival rate.
The UCLA team thought that maybe pesky cancer stem cells were to blame for the aggressive and resistant nature of these head and neck tumors. In a study published in Cell Stem Cell, they developed a mouse model of head and neck carcinoma and isolated cancer stem cells from the tumors of these mice. When they studied these stem cells, they found that they expressed unique proteins compared to non-cancer cells. These included Bmi1, a well-known stem cell protein, and AP-1, a transcription factor protein that regulates other cancer genes.
After identifying the culprits, the team developed a new combination strategy that targeted the cancer stem cells while also killing off the tumors using chemotherapy drugs.
In a UCLA Newsroom press release, the lead scientist on the study Dr. Cun-Yu Wang explained the importance of their study for the future treatment of cancer and solid tumors:
“This study shows that for the first time, targeting the proliferating tumor mass and dormant cancer stem cells with combination therapy effectively inhibited tumor growth and prevented metastasis compared to monotherapy in mice. Our discovery could be applied to other solid tumors such as breast and colon cancer, which also frequently metastasizes to lymph nodes or distant organs.”
Geoff Lomax is a Senior Officer of CIRM’s Strategic Initiatives.
California is one of the world-leaders in advancing stem cell research towards treatments and cures for patients with unmet medical needs. California has scientists at top universities and companies conducting cutting edge research in regenerative medicine. It also has CIRM, California’s Stem Cell Agency, which funds promising stem cell research and is advancing stem cell therapies into clinical trials. But the real clincher is that California has something that no one else has: a network of medical centers dedicated to stem cell-based clinical trials for patients. This first-of-its-kind system is called the CIRM Alpha Stem Cell Clinics Network.
Get to Know Our Alpha Clinics
In 2014, CIRM launched its Alpha Stem Cell Clinics Network to accelerate the development and delivery of stem cell treatments to patients. The network consists of three Alpha Clinic sites at UC San Diego, City of Hope in Duarte, and a joint clinic between UC Los Angeles and UC Irvine. Less than three years since its inception, the Alpha Clinics are conducting 34 stem cell clinical trials for a diverse range of diseases such as cancer, heart disease and sickle cell anemia. You can find a complete list of these clinical trials on our Alpha Clinics website. Below is an informational video about our Alpha Clinics Network.
So far, hundreds of patients have been treated at our Alpha Clinics. These top-notch medical centers use CIRM-funding to build teams specialized in overseeing stem cell trials. These teams include patient navigators who provided in-depth information about clinical trials to prospective patients and support them during their treatment. They also include pharmacists who work with patients’ cells or manufactured stem cell-products before the therapies are given to patients. And lastly, let’s not forget the doctors and nurses that are specially trained in the delivery of stem cell therapies to patients.
The Alpha Clinics Network also offers resources and tools for clinical trial sponsors, the people responsible for conducting the trials. These include patient education and recruitment tools and access to over 20 million patients in California to support successful recruitment. And because the different clinical trial sites are in the same network, sponsors can benefit from sharing the same approval measures for a single trial at multiple sites.
Looking at the big picture, our Alpha Clinics Network provides a platform where patients can access the latest stem cell treatments, and sponsors can access expert teams at multiple medical centers to increase the likelihood that their trial succeeds.
The Alpha Clinics Network is expanding
This collective expertise has resulted in a 3-fold (from 12 to 36) increase in the number of stem cell clinical trials at the Alpha Clinic sites since the Network’s inception. And the number continues to rise every quarter. Given this impressive track record, CIRM’s Board voted in February to expand our Alpha Clinics Network. The Board approved up to $16 million to be awarded to two additional medical centers ($8 million each) to create new Alpha Clinic sites and work with the current Network to accelerate patient access to stem cell treatments.
CIRM’s Chairman Jonathan Thomas explained,
“We laid down the foundation for conducting high quality stem cell trials when we started this network in 2014. The success of these clinics in less than three years has prompted the CIRM Board to expand the Network to include two new trial sites. With this expansion, CIRM is building on the current network’s momentum to establish new and better ways of treating patients with stem cell-based therapies.”
The Alpha Clinics Network plays a vital role in CIRM’s five-year strategic plan to fund 50 new clinical trials by 2020. In fact, the Alpha Clinic Network supports clinical trials funded by CIRM, industry sponsors and other sources. Thus, the Network is on track to becoming a sustainable resource to deliver stem cell treatments indefinitely.
In addition to expanding CIRM’s Network, the new sites will develop specialized programs to train doctors in the design and conduct of stem cell clinical trials. This training will help drive the development of new stem cell therapies at California medical centers.
Apply to be one our new Alpha Clinics!
For the medical centers interested in joining the CIRM Alpha Stem Cell Clinics Network, the deadline for applications is May 15th, 2017. Details on this funding opportunity can be found on our funding page.
The CIRM Team looks forward to working with prospective applicants to address any questions. The Alpha Stem Cell Clinics Network will also be showcasing it achievement at its Second Annual Symposium, details may be found on the City of Hope Alpha Clinics website.
- CIRM Alpha Clinics Network webpage
- Alpha Clinics expansion application page
- CIRM Alpha Stem Cell Clinics: Paving a Path to Cures
- Patients are the Heroes at the CIRM Alpha Stem Cell Clinics Symposium
About 120,000 people in the U.S. are on a waiting list for an organ donation and every day 22 of those people will die because there aren’t enough available organs. To overcome this organ donor crisis, bioengineers are working hard to develop 3D printing technologies that can construct tissues and organs from scratch by using cells as “bio-ink”.
Though each organ type presents its own unique set of 3D bioprinting challenges, one key hurdle they all share is ensuring that the transplanted organ is properly linked to a patient’s circulatory system, also called the vasculature. Like the intricate system of pipes required to distribute a city’s water supply to individual homes, the blood vessels of our circulatory system must branch out and reach our organs to provide oxygen and nutrients via the blood. An organ won’t last long after transplantation if it doesn’t establish this connection with the vasculature.
In a recent UC San Diego (UCSD) study, funded in part by CIRM, a team of engineers report on an important first step toward overcoming this challenge: they devised a new 3D bioprinting method to recreate the complex architecture of blood vessels found near organs. This type of 3D bioprinting approach has been attempted by other labs but these earlier methods only produced simple blood vessel shapes that were costly and took hours to fabricate. The UCSD team’s home grown 3D bioprinting process, in comparison, uses inexpensive components and only takes seconds to complete. Wei Zhu, the lead author on the Biomaterials publication, expanded on this comparison in a press release:
“We can directly print detailed microvasculature structures in extremely high resolution. Other 3D printing technologies produce the equivalent of ‘pixelated’ structures in comparison and usually require … additional steps to create the vessels.”
As a proof of principle, the bioprinted vessel structures – made with two human cell types found in blood vessels – were transplanted under the skin of mice. After two weeks, analysis of the skin showed that the human grafts were thriving and had integrated with the mice’s blood vessels. In fact, the presence of red blood cells throughout these fused vessels provided strong evidence that blood was able to circulate through them. Despite these promising results a lot of work remains.
As this technique comes closer to a reality, the team envisions using induced pluripotent stem cells to grow patient-specific organs and vasculature which would be less likely to be rejected by the immune system.
“Almost all tissues and organs need blood vessels to survive and work properly. This is a big bottleneck in making organ transplants, which are in high demand but in short supply,” says team lead Shaochen Chen. “3D bioprinting organs can help bridge this gap, and our lab has taken a big step toward that goal.”
We eagerly await the day when those transplant waitlists become a thing of the past.
There are many challenges in taking even the most promising stem cell treatment and turning it into a commercial product approved by the Food and Drug Administration (FDA). One of the biggest is expertise. The scientists who develop the therapy may be brilliant in the lab but have little experience or expertise in successfully getting their work through a clinical trial and ultimately to market.
That’s why a team at U.C. Davis has just signed a deal with a startup company to help them move a promising stem cell treatment for arthritis, osteoporosis and fractures out of the lab and into people.
They plan to test a hybrid molecule called RAB-001 which has shown promise in helping direct mesenchymal stem cells (MSCs) – these are cells typically found in the bone marrow and fat tissue – to help stimulate bone growth and increase existing bone mass and strength. This can help heal people suffering from conditions like osteoporosis or hard to heal fractures. RAB-001 has also shown promise in reducing inflammation and so could prove helpful in treating people with inflammatory arthritis.
In a news article on the UC Davis website, Wei Yao, said RAB-001 seems to solve a problem that has long puzzled researchers:
“There are many stem cells, even in elderly people, but they do not readily migrate to bone. Finding a molecule that attaches to stem cells and guides them to the targets we need provides a real breakthrough.”
The UC Davis team already has approval to begin a Phase 1 clinical trial to test this approach on people with osteonecrosis, a disease caused by reduced blood flow to bones. CIRM is funding this work.
The RABOME team also hopes to test RAB-001 in clinical trials for healing broken bones, osteoporosis and inflammatory arthritis.
To help other researchers overcome these same regulatory hurdles in developing stem cell therapies CIRM created the Stem Cell Center with QuintilesIMS, a leading integrated information and technology-enabled healthcare service provider that has deep experience and therapeutic expertise. The Stem Cell Center will help researchers overcome the challenges of manufacturing and testing treatments to meet FDA standards, and then running a clinical trial to test that therapy in people.
March is Multiple Sclerosis month. In honor of MS patients and research, we are featuring a guest blog from scientist and communicator Hamideh Emrani. Thoughts expressed here are not necessarily those of CIRM.
If you are reading this post, other than out of curiosity, chances are that you know someone who has been affected by Multiple Sclerosis (MS). This unpredictable and at times confusing disease has affected too many people in my circle of friends and family. I personally have spent hours reading about it and reading about possible treatments.
For instance, M, a really close friend of mine woke up one day and everything was blurry. She could see but it seemed as if there was a thick fog covering everything. After seeing her optometrist and being evaluated via multiple tests and an MRI scan, she was diagnosed with MS. The reason behind her blurred vision was inflammation of her optic nerves.
Why do MS symptoms happen?
The nerve cells in the brain and spinal cord are connected through cellular extensions. Each cell has one long cellular extension at one end, called an axon, that looks similar to an electrical wire. Axons relay information using neural signals from one cell to another. Just as an electrical wire has a protective plastic cover to avoid leakage of electricity, these axons, are covered with a protective layer of a special fat called myelin.
In MS, a patient’s immune cells start to attack this protective layer in the central nervous system: the optic nerves, brain, and the spinal cord. They also attack the cells that produce myelin (called oligodendrocytes) and the injured nerve axon fibers. This results in de-myelination or the loss of myelin; and eventual deterioration and damage of the nerve axons. In turn, multiple scar tissues form on the damaged areas on nerves that can be seen through MRI, hence the name “multiple sclerosis” with sclerosis meaning scar tissue.
Generally, the demyelination and scar tissue will cause communication problems among nerves and the symptoms vary in each patient making it a complicated disease to treat. Some common resulting symptoms include excessive fatigue, pain, blurred vision, walking difficulties, muscle stiffness and changes in brain-based skills such as memory and problem solving.
Depending on the stage of the disease and the extent of the damage, the disease has been categorized to four different courses.MS Type Description Clinically Isolated Syndrome (CIS) The person has had one episode of neurological symptoms that may or may not be accompanied by damages seen in an MRI scan.
Relapsing remitting MS (RRMS) The most common type of MS, which is characterized by clearly defined periods of neurologic inflammation called “MS attacks” that can be followed by periods of partial or complete recovery. The person might be completely symptom free during these remission times. Secondary progressive MS (SPMS) Many patients with RRMS over time transition to SPMS where there is no recovery from the symptoms and disability accumulates.
Primary progressive MS (PPMS) There are no remissions from the onset of the disease and disability caused by disease activity worsens over time.
What is the cause of MS?
MS is affecting a growing number of human populations. While the jury is still out to define the main cause, many scientists believe that various factors play a role such as genetic predisposition, viral and bacterial infections, and environmental cues. MS is mostly prominent in countries in the Northern hemisphere and colder climates. It affects more women than men, and is mostly diagnosed between the age of 35-50.
Treatments for MS
Unfortunately, there is no cure for MS at the moment. The drugs that are available, called MS modifying treatments, try to prevent the progression of the disease but they don’t reverse it. Instead, the drugs mostly modulate the immune system to avoid further attacks or treat symptoms such as fatigue, pain, and bladder issues that are caused by the damage.
How do stem cells come into picture?
Stem cells are unique cells with the ability to both self-renew and specialize into different cell types. This amazing regeneration ability has turned them into great sources for designing treatment strategies to replace the damaged cells in MS. Two stem cell treatment approaches for MS are currently in development. In one, the researchers try to reboot or modulate the patient’s immune system to prevent it from attacking the nerve cells. In the other, scientists focus on using stem cells to make oligodendrocytes to try and regenerate and repair lost and injured nervous tissue.
Overview of Recent Clinical Trials
The most common stem cells used in clinical trials are the blood, or haematopoietic stem cells (HSCs) which are isolated from the bone marrow. Haematopoietic stem cell transplants (HSCT) have been used for decades to treat blood cancers such as leukemias, but the first time they were studied for treating MS was in the 1990s.
In this method, the patient’s HSCs are collected from the bone marrow and stored. Then, the patient’s immune system, including the bone marrow, is completely depleted through chemotherapy. Finally, the stem cells are transplanted back into the body and after a few months eventually build up a new immune system.
Just last month, Dr. Paolo Muraro et al. published a report that reviews such clinical trials and the long-term outcomes for the patients. They evaluated data for 281 patients from 25 centers in 13 countries that were followed an average of 6.5 years after the transplant. At the end they conclude that almost half of the patients receiving HSCT did not have any progression of the disease. And, younger patients with the most common form of MS, RRMS, who had less disability going into the trial, and had gone through less disease modifying treatments had a better outcome. (73% were progression free at the 5 year mark).
Additionally, over the past two years three separate phase two clinical trials in Northern America have reported results:
- In the HALT-MS trial, a small number (24) of patients with, RRMS, whose disease was not controlled by any medications, underwent HSCT. After 5 years, 91.3% of the patients did not show any sign of disease progression.
- In June 2016, a Canadian team of researchers reported the results of a long term follow up of an aHSCT trial (the “a” stands for autologous, meaning it used the patient’s own cells) on 24 patients whose MS had progressed even after receiving conventional treatments. After up to 13 years after the transplantation, no relapses were evident, and 35% of the patients experienced reversals in their level of disability.
- Back in 2015, Burt et al. reported their HSCT treatment regimen for 123 RRMS patients and their follow up of up to 4 years. In their study, instead of completely depleting the patient’s immune system, they just suppressed it and performed the transplants. Their data suggest that there was no disease progression in 87% of individuals who had MS for less than 10 years.
Will Stem Cells be used for treatment of MS in the near future?
Even though the initial results of the HSCT clinical trials sound promising, the risks that are involved are not easy to ignore. In all the mentioned trials, there were side effects related to the transplant. There were also a total of nine deaths reported in all the studies combined (since 1990s). However, most of these deaths occurred before the year of 2000 and they were attributed to transplantation techniques and patient selection methods. Over the years, researchers have been working hard to fine tune the techniques and made the procedure safer. But even now it is important for the patients to weigh the benefits and the risks before undergoing the procedure.
That’s why neurologists and stem cell scientists do not currently recommend blood stem cell transplants as the top-of-the-line treatment option for most MS patients. Other types of stem cells are being investigated for their potential in deriving oligodendrocytes and nerve cells to re-myelinate and repair the damaged ones. However, they are still in development and have not reached a clinical trial in people.
At the moment, many stem cell treatment approaches are all at the experimental level and more research is needed to completely prove them to be safe and effective. There are many trusted sources to get information from and the international society for stem cell research (ISSCR) has produced a great nine step guideline for patients and family members considering stem cell treatments. Also the national MS society website is a great resource for learning more about Multiple Sclerosis, including participating in clinical trial studies.
Hamideh Emrani is a science and technology communicator in Toronto, Canada. She is a graduate of UC Berkeley and has a Masters degree from the University of Toronto. You can follow Hamideh on Twitter.
Building an embryo in the lab from stem cells
The human body has been studied for centuries yet little is known about the first 14 days of human development when the fertilized embryo implants into the mother’s uterus and begins to divide and grow. Being able to precisely examine this critical time window may help researchers better understand why 75% of conceptions never implant and why 30% of pregnancies end in miscarriage.
This lack of knowledge is due in part to a lack of embryos to study. Researchers rely on embryos donated by couples who’ve gone through in vitro fertilization to get pregnant and have left over embryos that are otherwise discarded. Using mouse stem cells, a research team from Cambridge University reports today in Nature that they’ve generated a cellular structure that has the hallmarks of a fertilized embryo.
This technique has been tried before without success. The breakthrough here was in the types of cells used. Rather that only relying on embryonic stems cells (ESCs), this study also included extra-embryonic trophoblast stem cells (TSCs), the cell type that goes on to form the placenta.
When grown on a 3D scaffold made from biological materials, the two cell types self-organized themselves into a pattern that closely resembles the early development of a true embryo. In a press release that was picked up by many media outlets, senior author Zernicka-Goetz spoke about the importance of including both TSCs and ESCs:
“We knew that interactions between the different types of stem cell are important for development, but the striking thing that our new work illustrates is that this is a real partnership – these cells truly guide each other. Without this partnership, the correct development of shape and form and the timely activity of key biological mechanisms doesn’t take place properly.”
The researchers think that lab-made embryos from mouse or human stem cells have little chance of developing into a fetus because other cell types critical for continued growth are not included. And there’s much to be learned by focusing on these very early events:
“We are very optimistic that this will allow us to study key events of this critical stage of human development without actually having to work on embryos. Knowing how development normally occurs will allow us to understand why it so often goes wrong,” says Zernicka-Goetz.
Reviving old blood stem cells, part 1: repair the garbage collectors
One of the reasons that our bodies begin to deteriorate in old age is a weakening, dysfunctional immune system that increases the risk for serious infection, blood cancers and chronic inflammatory diseases like atherosclerosis (hardening of the arteries). Reporting this week in Nature, a UCSF research team presents evidence that a breakdown in our cell’s natural garbage collecting system may be partially to blame.
The team focused on a process called autophagy (literally meaning self “auto”-eating “phagy”) that keeps cells functioning properly by degrading faulty proteins and cellular structures. In particular, they examined autophagy in blood-forming stem cells, which give rise to all the cell types of the immune system. They found that autophagy was not working in 70 percent of blood stem cells from old mice. And these cells had all the hallmarks of an old cell. And the other 30 percent? In those cells, autophagy was fully functional and they looked like blood stem cells found in young mice.
The team went on to show that in blood stem cells, autophagy had an additional role that until now had not been observed: it helped slow the activity of the stem cells back to its default state by gobbling up excess mitochondria, the structures that produces a cell’s energy needs. Without this quieting of the stem cell, the over-active mitochondria led to chemical modification of the cell’s DNA that disrupted the blood stem cells’ ability to give rise to a proper balance of immune cells. In fact, young mice with genetic modifications that block autophagy generated blood stem cells with these old age-related characteristics.
But the researchers were also able to restore autophagy in blood stem cells collected from old mice by adding various drugs. Team lead Emmanuelle Passegué is optimistic this result could be translated into a therapeutic approach:
“This discovery might provide an interesting therapeutic angle to use in re-activating autophagy in all of the old HSCs, to slow the aging of the blood system and to improve engraftment during bone marrow or HSC transplantation,” Passegué said in a university press release.
Reviving old blood stem cells, part 2: fix the aging neighborhood
Another study this week focused on age-related disruptions in the function of blood stem cells but in this case an aging neighborhood is to blame. Blood stem cells form and hang out in areas of the bone marrow called niches. Researchers at the Cincinnati Children’s Hospital Medical Center and the University of Ulm in Germany reported this week in EMBO that the age of the niche affects blood stem cell function.
When blood stem cells from two-year old mice were transplanted into the bone marrow of eight-week old mice, the older stem cells took on characteristics of young stem cells including an enhance ability to form all the different cell types of the immune system. In trying to understand what was going on, the researchers focused on a bone marrow cell called an osteoblast which gives rise to bone. Osteoblasts produce osteopontin, a protein that plays an important role in the structure of the bone marrow. The team showed that as the bone marrow ages, osteopontin levels go down. And this reduction had effects on the health of blood stem cells. But, as team lead Hartmut Geiger mentions in a press release, this impact could be reversed which points to a potential new therapeutic strategy for age-related disease:
“We show that the place where HSCs form in the bone marrow loses osteopontin upon aging, but if you give back the missing protein to the blood-forming cells they suddenly rejuvenate and act younger. Our study points to exciting novel ways to have a better immune system and possibly less blood cancer upon aging by therapeutically targeting the place where blood stem cells form.”
It’s never too early to start learning.
When it comes to teaching science to kids, here’s my advice: don’t shy away from talking about topics like mitochondria or nuclei. Children are curious and intelligent. They can understand complex scientific concepts if you engage them in the right way. So it’s time to set aside the baby talk and educate young minds about science early so that they can understand their own biology and the world around them.
There are many ways to educate kids about science, but a tried and true method is children’s picture books. Images capture children’s attention and tell a visual story that connects with their brains better than words can on their own.
One of my favorite children’s science books is a series called “Think-A-Lot-Tots.” They are written for babies, toddlers and kids and have beautiful hand-drawn illustrations. The author, Dr. Thomai Dion, is a pharmacist and science writer who was inspired to write this series to satisfy her young son’s curiosity for science. So far she has written books about animal cells, neurons, microorganisms, and just this week, she published a new book about stem cells!
I have to admit that I’m to blame for this new stem cell book. When I first read her stories, I was so excited by how simply and elegantly she wrote about neurons, that I started daydreaming about a children’s book on stem cells. I contacted Thomai and asked her whether she wanted to collaborate on a stem cell book. She was very eager, so I wrote the initial script and Thomai used her artistic expertise to visualize my ideas. Fast forward three months and Thomai has turned my dream into a wonderful book that I can share with my family and friends with kids!
The stem cell book covers the basics, starting with what a stem cell is and then expanding into the different types of stem cells in the body. By the end, kids will understand that they come from embryonic stem cells and that they have adult stem cells in their body that keep them healthy.
Below are a few pages from Think-A-Lot-Tots: Stem Cells and also a short interview where Thomai explains her inspiration behind her children’s book series and her newest edition on stem cells.
Interview with Author Thomai Dion
Q: Tell us about the mission of your Think-A-Lot-Tots series.
TD: The mission for my “Think-A-Lot-Tots” series is to introduce science education to our youngest thinkers in a fun, approachable and engaging way. My books do not strive to make an expert of the reader; rather, they provide an overview of a seemingly abstract and advanced scientific concept otherwise reserved for “older children” in an effort to show that babies, toddlers and younger kids can not only retain but also enjoy these same topics. My books focus on building scientific vocabulary, promoting STEM education at a very young age and sparking a love of learning as soon as possible.
Q: How did you get interested in writing children’s books about science?
TD: It was my son’s questions about the world around him that made me want to teach him as much as I could about all that I could. Similar to other children, several of his questions would revolve around topics such as why the sky is blue and why the grass is green. He has also pleasantly surprised me with several very insightful inquiries such as why do “tall trees” lose their leaves but pines trees do not, as well as “how do my eyes see?”. His natural inclination to ask “why” coupled with an insatiable desire to learn inspired me to teach him about science-focused concepts beyond what is readily seen such as the cell, the neuron and microorganisms. I created my first book as a helpful way for him and I to talk about topics like the cell, and I thought since I was making this available to my family, I may as well make it available to others. As such, my first book was created and 4 others have followed with a 5th nearly finished.
Q: Why were you inspired to write a book about stem cells?
TD: My first children’s science book focused on the parts of the cell, providing an overview of the cell membrane, the nucleus, mitochondria and others. My second book focused on the neuron, which discussed not only its different parts but also its special function within our bodies. I found that I enjoyed not only talking about what a cell or neuron was but also why it was important, and so I began thinking about what other ideas I could write about in this manner.
I am a pharmacist by trade and although familiar with stem cells, I was not initially as knowledgeable as I would have liked to be about what their function was within the body, what types of work were currently being done with regards to their research, and what a significant impact they could have on science and medicine. I learned more about all of this as I connected with folks within the field who focused on stem cell research, and only then did I realize how important it was for not only myself to understand stem cells but also our future big thinkers.
I was thrilled when you reached out to me with the idea of writing a book about stem cells and am so thankful for the guidance and expertise you provided with the creation of “Think-A-Lot-Tots: Stem Cells”. My little one will be 4-years-old soon and we’ve read the book together several times. To hear a child want to talk about and exclaim “stem cells!” before they have even begun elementary school is so wonderful!
Q: What other types of science books are you planning to write?
TD: I admittedly have an entire list of topics that I’d like to write about for children’s STEM education. As a medical professional, most of these topics can be found within biology, anatomy and physiology, although I do have some ideas that introduce concepts within chemistry and other areas as well. I am a few days away from officially releasing a STEM coloring book and it would be a very exciting area to explore further with additional coloring and activity books in the future. I also currently have a children’s notebook available that outlines the steps found within the scientific method and I’d love to continue creating hands-on learning tools in addition to read-along books.
Q: What are your insights for the best ways to teach young kids science?
TD: I think we vastly underestimate our children’s ability to learn about their world. Provided the child has an interest in learning about a topic, I don’t see any limitation in explaining the facets of that topics or introducing the terminology typically associated with its discussion. I truly believe there is no difference between teaching a child the word “ball” and the word “nucleus”; rather, it builds familiarity with the term and could even be associated with enjoyable memories if presented in a fun and engaging way.
Similarly to teaching about scientific terminology, science as a whole does not have to be limited to an academic setting and only after a certain age. In reality, children are naturally-born scientists, eager to inquire about any and everything around them from the very beginning of their childhood. I recently wrote an article discussing this concept that was published in Ar Magazine entitled “The Science of Why and its Impact on Children’s Learning”.
In summary and to quote part of this article, I note that “My son and I talk together constantly throughout the day about his observations, what he thinks of this leaf or that rock. I also read to him daily either the books that I created myself as well as those from other talented authors and illustrators. To hinder my child’s natural aptitude towards science would be to mute his interest in the world around him. More simply stated, my brushing-off his questions would stifle his drive to learn. In my humble opinion, I cannot bring myself to do that.” In short, I would say the best ways to teach young kids about science would be to: Talk together. Talk often. Talk about it all.
Though the celebrities at Sunday’s Academy Awards worked hard to sport unique clothing and hair styles, I bet many had something in common: Botox injections. Botox, an FDA-approved, marketed form of Botulism neurotoxin, is well known for its wrinkle reducing effects. The neurotoxin’s other claim to fame is the fact that it’s the most lethal, naturally occurring poison known. Inhaling a minuscule amount – just 0.0000007 grams! – is enough to kill a 150 pound person.
Much smaller, non-lethal doses of Botulism neurotoxin are obviously used for its cosmetic application. It’s also used to treat a wide range of disorders including back pain, migraines and muscle spasms related to stroke and cerebral palsy. Because the toxin is produced naturally by the Clostridium botulinum bacteria, the amount of toxin can vary in each batch during the manufacturing process. So, it’s critical to carefully analyze the Botulism neurotoxin dose. The standard test which has been around since the 1920’s is the mouse bioassay. During the test, increasing concentrations of the neurotoxin are injected into mice which are then observed for signs of paralysis (Botulism neurotoxin acts by blocking communication between nerves and muscle).
As you might expect, the lab mice suffer during the test, sometimes suffocating during the process. Because of the large market for these Botulism neurotoxin-based products, it’s estimated that about 600,000 laboratory mice in US and Europe are killed via the mouse bioassay each year. Though the media often portrays scientists as callous, cold-hearted people that couldn’t care less about the welfare of their lab animals, in reality, it’s just the opposite. Case in point: a research group at the University of Bern in Switzerland reported this week in Frontiers in Pharmacology that they have devised an alternative system that could help make this mouse bioassay obsolete.
To set up this new assay system, the researchers relied on mouse embryonic stem cells. The researchers added chemicals to the cells, stimulating them to transform into nerve cells, or neurons. These stem cell-derived neurons were placed in specialized petri dishes that look something like a computer chip. Wired with mini electrodes, the lab dishes allowed the continuous recording of electrical signals generated by the neurons. Adding small doses of Botox to the cells, the scientists could detect a shutdown of the neuron signaling which is the same underlying effect that causes paralysis in the mouse bioassay.
This sensitive test could have applications beyond the detection of Botulism neurotoxin. The electrode dishes are easy to scale up and do not require highly trained staff. So, without the need for expensive animal testing, this system could be used as a high throughput drug screening platform to find other substances that have beneficial effects on neuron signaling.
One of the goals we set ourselves at CIRM in our 2016 Strategic Plan was to fund 50 new clinical trials over the next five years, including ten rare or orphan diseases. Since then we have funded 13 new clinical trials including four targeting rare diseases (retinitis pigmentosa, severe combined immunodeficiency, ALS or Lou Gehrig’s disease, and Duchenne’s Muscular Dystrophy). It’s a good start but clearly, with almost 7,000 rare diseases, this is just the tip of the iceberg. There is still so much work to do.
And all around the world people are doing that work. Today we have asked Emily Walsh, the Community Outreach Director at the Mesothelioma Cancer Alliance, to write about the efforts underway to raise awareness about rare diseases, and to raise funds for research to develop new treatments for them.
“February 28th marks the annual worldwide event for Rare Disease Day. This is a day dedicated to raising awareness for rare diseases that affect people all over the world. The campaign works to target the general public as well as policy makers in hopes of bringing attention to diseases that receive little attention and funding. For the year 2017 it was decided that the focus would fall on “research,” with the slogan, “With research, possibilities are limitless.”
Getting involved for Rare Disease Day means taking this message and spreading it far and wide. Awareness for rare diseases is extremely important, especially among researchers, universities, students, companies, policy makers, and clinicians. It has long been known that the best advocates for rare diseases are the patients themselves. They use their specific perspectives to raise their voice, share their story, and shed light on the areas where additional funding and research are most necessary.
To see how you can help support the Rare Disease Day efforts this year, click here.
Groups like the Mesothelioma Cancer Alliance and the Mesothelioma Group are adding their voices to the cause to raise awareness about mesothelioma cancer, a rare form of cancer caused by exposure and inhalation of airborne asbestos fibers
Rare diseases affect 300 million people worldwide, but only 5% of them have an FDA approved treatment or cure. Malignant mesothelioma is among the 95 percent that doesn’t have a treatment or cure.
Asbestos has been used throughout history in building materials because of its fire retardant properties. Having a home with asbestos insulation, ceiling tiles, and roof shingles meant that the house was safer. However, it was found that once asbestos crumbled and became powder-like, the tiny fibers could become airborne and be inhaled and lodge themselves in lung tissue causing mesothelioma. The late stage discovery of mesothelioma is often what causes it to have such a high mortality rate. Symptoms can have a very sudden onset, even though the person may have been exposed decades prior.
Right now, treatment for mesothelioma includes the usual combination of chemotherapy, radiation, and surgery, but researchers are looking at other approaches to see if they can be more effective or can help in conjunction with the standard methods. For example one drug, Defactinib, has shown some promise in inhibiting the growth and spread of cancer stem cells – these are stem cells that can evade chemotherapy and cause patients to relapse.”
Some people might ask why spend limited resources on something that affects so few people. But the lessons we learn in developing treatments for a rare disease can often lead us to treatments for diseases that affect many millions of people.
But numbers aside, there is no hierarchy of need, no scale to say the suffering of people with Huntington’s disease is any greater or less than that of people with Alzheimer’s. We are not in the business of making value judgements about who has the greatest need. We are in the business of accelerating treatments to patients with unmet medical needs. And those suffering from rare disease are very clearly people in need.
- Rare Disease Day (2016), A Chance to Raise Awareness and Hope
- Rare Diseases Are Not So Rare
- How Research on a Rare Disease Turned into a Faster Way to Make Stem Cells
- Making a Deposit in the Bank: Using Stem Cells from Children with Rare Diseases to Find New Treatments
Scientists are often stereotyped as serious, focused individuals who spend most of their time pursuing their science with little time for anything else. Their research often is complex and hard for non-scientists to wrap their minds around. I’ve often heard my friends describe to me what they thought I did every day when I was in the lab. It was like a science fantasy story involving beakers full of brightly colored chemicals, explosions, and at the end, a cure for Parkinson’s disease…
But I am going to tell you a little known secret: scientists are normal people like everyone else. They aren’t magicians with special powers, and they know how to have fun while doing their research. The problem is that the public doesn’t know this because they don’t have the opportunity to visit a research laboratory and see scientists in action.
UC Davis Professor Paul Knoepfler is addressing this issue with his new lab tour video contest that he recently announced on his blog, The Niche. He’s asking scientists to make short videos of their daily lives in the lab and post them on Twitter with the hashtag #labvideocontest. The winner will receive a cash prize and “free PR for their lab”. The videos can be serious or funny, but Paul asks contestants to use their imagination and think out of the box.
This contest will not only be a fun way for scientists to talk about their research and what they do every day, but it will also benefit the public who will get an inside view of what it’s like to be a scientist. The goal of science communications is to make science relatable to everyone, and this video contest on social media is a great example of new ways that scientists can connect with the public and make science more approachable.
You scientists out there can learn more about Paul’s contest and how to participate on his blog. The deadline to submit lab videos is March 15th, so you better get to work!
And if you need a place to start, watch our recent video featuring the McDevitt lab, a stem cell bioengineering lab at the Gladstone Institutes.
Stem cells stories that caught our eye: switching cell ID to treat diabetes, AI predicts cell fate, stem cell ALS therapy for Canada
Treating diabetes by changing a cell’s identity. Stem cells are an ideal therapy strategy for treating type 1 diabetes. That’s because the disease is caused by the loss of a very specific cell type: the insulin-producing beta cell in the pancreas. So, several groups are developing treatments that aim to replace the lost cells by transplanting stem cell-derived beta cells grown in the lab. In fact, Viacyte is applying this approach in an ongoing CIRM-funded clinical trial.
In preliminary animal studies published late last week, a Stanford research team has shown another approach may be possible which generates beta cells inside the body instead of relying on cells grown in a petri dish. The CIRM-funded Cell Metabolism report focused on alpha cells, another cell type in pancreas which produces the hormone glucagon.
After eating a meal, insulin is critical for getting blood sugar into your cells for their energy needs. But glucagon is needed to release stored up sugar, or glucose, into your blood when you haven’t eaten for a while. The research team, blocked two genes in mice that are critical for maintaining an alpha cell state. Seven weeks after inhibiting the activity of these genes, the researchers saw that many alpha cells had converted to beta cells, a process called direct reprogramming.
Does the same thing happen in humans? A study of cadaver donors who had been recently diagnosed with diabetes before their death suggests the answer is yes. An analysis of pancreatic tissue samples showed cells that produced both insulin and glucagon, and appeared to be in the process of converting from beta to alpha cells. Further genetic tests showed that diabetes donor cells had lost activity in the two genes that were blocked in the mouse studies.
It turns out that there’s naturally an excess of alpha cells so, as team lead Seung Kim mentioned in a press release, this strategy could pan out:
“This indicates that it might be possible to use targeted methods to block these genes or the signals controlling them in the pancreatic islets of people with diabetes to enhance the proportion of alpha cells that convert into beta cells.”
Using computers to predict cell fate. Deep learning is a cutting-edge area of computer science that uses computer algorithms to perform tasks that border on artificial intelligence. From beating humans in a game of Go to self-driving car technology, deep learning has an exciting range of applications. Now, scientists at Helmholtz Zentrum München in Germany have used deep learning to predict the fate of cells.
The study, published this week in Nature Methods, focused on blood stem cells also called hematopoietic stem cells. These cells live in the bone marrow and give rise to all the different types of blood cells. This process can go awry and lead to deadly disorders like leukemia, so scientists are very interested in exquisitely understanding each step that a blood stem cell takes as it specializes into different cell types.
Researchers can figure out the fate of a blood stem cells by adding tags, which glow with various color, to the cell surface . Under a microscope these colors reveal the cells identity. But this method is always after the fact. There no way to look at a cell and predict what type of cell it is turning into. In this study, the team filmed the cells under a microscope as they transformed into different cell types. The deep learning algorithm processed the patterns in the cells and developed cell fate predictions. Now, compared to the typical method using the glowing tags, the researchers knew the eventual cell fates much sooner. The team lead, Carsten Marr, explained how this new technology could help their research:
“Since we now know which cells will develop in which way, we can isolate them earlier than before and examine how they differ at a molecular level. We want to use this information to understand how the choices are made for particular developmental traits.”
Stem cell therapy for ALS seeking approval in Canada. (Karen Ring) Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease that kills off the nerve cells responsible for controlling muscle movement. Patients with ALS suffer from muscle weakness, difficulty in speaking, and eventually breathing. There is no cure for ALS and the average life expectancy after diagnosis is just 2 – 5 years. But companies are pursuing stem cell-based therapies in clinical trials as promising treatment options.
One company in particular, BrainStorm Cell Therapeutics based in the US and Israel, is testing a mesenchymal stem cell-based therapy called NurOwn in ALS patients in clinical trials. In their Phase 2 trials, they observed clinical improvements in slowing down the rate of disease progression following the stem cell treatment.
In a recent update from our friends at the Signals Blog, BrainStorm has announced that it is seeking regulatory approval of its NurOwn treatment for ALS patients in Canada. They will be working with the Centre for Commercialization of Regenerative Medicine (CCRM) to apply for a special regulatory approval pathway with Health Canada, the Canadian government department responsible for national public health.
In a press release, BrainStorm CEO Chaim Lebovits, highlighted this new partnership and his company’s mission to gain regulatory approval for their ALS treatment:
“We are pleased to partner with CCRM as we continue our efforts to develop and make NurOwn available commercially to patients with ALS as quickly as possible. We look forward to discussing with Health Canada staff the results of our ALS clinical program to date, which we believe shows compelling evidence of safety and efficacy and may qualify for rapid review under Canada’s regulatory guidelines for drugs to treat serious or life-threatening conditions.”
Stacey Johnson who wrote the Signals Blog piece on this story explained that while BrainStorm is not starting a clinical trial for ALS in Canada, there will be significant benefits if its treatment is approved.
“If BrainStorm qualifies for this pathway and its market authorization request is successful, it is possible that NurOwn could be available for patients in Canada by early 2018. True access to improved treatments for Canadian ALS patients would be a great outcome and something we are all hoping for.”
CIRM is also funding stem cell-based therapies in clinical trials for ALS. Just yesterday our Board awarded Cedars-Sinai $6.15 million dollars to conduct a Phase 1 trial for ALS patients that will use “cells called astrocytes that have been specially re-engineered to secrete proteins that can help repair and replace the cells damaged by the disease.” You can read more about this new trial in our latest news release.