CIRM weekly stem cell roundup: stomach bacteria & cancer; vitamin C may block leukemia; stem cells bring down a 6’2″ 246lb football player

gastric

This is what your stomach glands looks like from the inside:  Credit: MPI for Infection Biology”

Stomach bacteria crank up stem cell renewal, may be link to gastric cancer.

The Centers for Disease Control and Prevention estimate that two-thirds of the world’s population is infected with H. pylori, a type of bacteria that thrives in the harsh acidic conditions of the stomach. Data accumulated over the past few decades shows strong evidence that H. pylori infection increases the risk of stomach cancers. The underlying mechanisms of this link have remained unclear. But research published this week in Nature suggests that the bacteria cause stem cells located in the stomach lining to divide more frequently leading to an increased potential for cancerous growth.

Tumors need to make an initial foothold in a tissue in order to grow and spread. But the cells of our stomach lining are replaced every four days. So, how would H. pylori bacterial infection have time to induce a cancer? The research team – a collaboration between scientists at the Max Planck Institute in Berlin and Stanford University – asked that question and found that the bacteria are also able to penetrate down into the stomach glands and infect stem cells whose job it is to continually replenish the stomach lining.

Further analysis in mice revealed that two groups of stem cells exist in the stomach glands – one slowly dividing and one rapidly dividing population. Both stem cell populations respond similarly to an important signaling protein, called Wnt, that sustains stem cell renewal. But the team also discovered a second key stem cell signaling protein called R-spondin that is released by connective tissue underneath the stomach glands. H. pylori infection of these cells causes an increase in R-spondin which shuts down the slowly dividing stem cell population but cranks up the cell division of the rapidly dividing stem cells. First author, Dr. Michal Sigal, summed up in a press release how these results may point to stem cells as the link between bacterial infection and increased risk of stomach cancer:

“Since H. pylori causes life-long infections, the constant increase in stem cell divisions may be enough to explain the increased risk of carcinogenesis observed.”

vitamin-c-1200x630

Vitamin C may have anti-blood cancer properties

Vitamin C is known to have a number of health benefits, from preventing scurvy to limiting the buildup of fatty plaque in your arteries. Now a new study says we might soon be able to add another benefit: it may be able to block the progression of leukemia and other blood cancers.

Researchers at the NYU School of Medicine focused their work on an enzyme called TET2. This is found in hematopoietic stem cells (HSCs), the kind of stem cell typically found in bone marrow. The absence of TET2 is known to keep these HSCs in a pre-leukemic state; in effect priming the body to develop leukemia. The researchers showed that high doses of vitamin C can prevent, or even reverse that, by increasing the activity level of TET2.

In the study, in the journal Cell, they showed how they developed mice that could have their levels of TET2 increased or decreased. They then transplanted bone marrow with low levels of TET2 from those mice into healthy, normal mice. The healthy mice started to develop leukemia-like symptoms. However, when the researchers used high doses of vitamin C to restore the activity levels of TET2, they were able to halt the progression of the leukemia.

Now this doesn’t mean you should run out and get as much vitamin C as you can to help protect you against leukemia. In an article in The Scientist, Benjamin Neel, senior author of the study, says while vitamin C does have health benefits,  consuming large doses won’t do you much good:

“They’re unlikely to be a general anti-cancer therapy, and they really should be understood based on the molecular understanding of the many actions vitamin C has in cells.”

However, Neel says these findings do give scientists a new tool to help them target cells before they become leukemic.

Jordan reed

Bad toe forces Jordan Reed to take a knee: Photo courtesy FanRag Sports

Toeing the line: how unapproved stem cell treatment made matters worse for an NFL player  

American football players are tough. They have to be to withstand pounding tackles by 300lb men wearing pads and a helmet. But it wasn’t a crunching hit that took Washington Redskins player Jordan Reed out of the game; all it took to put the 6’2” 246 lb player on the PUP (Physically Unable to Perform) list was a little stem cell injection.

Reed has had a lingering injury problem with the big toe on his left foot. So, during the off-season, he thought he would take care of the issue, and got a stem cell injection in the toe. It didn’t quite work the way he hoped.

In an interview with the Richmond Times Dispatch he said:

“That kind of flared it up a bit on me. Now I’m just letting it calm down before I get out there. I’ve just gotta take my time, let it heal and strengthen up, then get back out there.”

It’s not clear what kind of stem cells Reed got, if they were his own or from a donor. What is clear is that he is just the latest in a long line of athletes who have turned to stem cells to help repair or speed up recovery from an injury. These are treatments that have not been approved by the Food and Drug Administration (FDA) and that have not been tested in a clinical trial to make sure they are both safe and effective.

In Reed’s case the problem seems to be a relatively minor one; his toe is expected to heal and he should be back in action before too long.

Stem cell researcher and avid blogger Dr. Paul Knoepfler wrote he is lucky, others who take a similar approach may not be:

“Fortunately, it sounds like Reed will be fine, but some people have much worse reactions to unproven stem cells than a sore toe, including blindness and tumors. Be careful out there!”

 

Brain stem cells unintentionally talk with brain tumors, allowing their spread

A stem cell’s capacity to lay quiet and, when needed, to self-renew plays a key role in restoring and maintaining the health of our organs. Unfortunately, cancer stem cells possess that same property allowing them to evade radiation and chemotherapy treatments which leads to tumor regrowth. And a CIRM-funded study published today in Cell shows the deviousness of these cancer cells goes even further. The Stanford research team behind the study found evidence that brain stem cells, which normally guide brain development and maintenance, unintentionally communicate with brain cancer cells in deadly tumors, called gliomas, providing them a means to invade other parts of the brain. But the silver lining to this scary insight is that it may lead to new treatment options for patients.

High grade gliomas do not end well
The most aggressive forms of glioma are called high grade gliomas and they carry devastating prognoses. For instance, the most common form of these tumors in children has a median survival of just 9 months with a 5-year survival of less than 1%. Surgery or anti-cancer therapies may help for a while but the tumor inevitably grows back.

MRI image of high grade glioma brain tumor (white mass on left). Image: Wikipedia

Researchers have observed that gliomas typically originate in the brain stem and very often invade a brain stem cell-rich area, called the subventrical zone (SVZ), that provides a space for the therapy-resistant cancer stem cells to hole up. This path of tumor spread is associated with a shorter time to relapse and poorer survival but the exact mechanism wasn’t known. The Stanford team hypothesized that SVZ brain stem cells release some factor that attracts the gliomas to preferentially invade that part of the brain.

To test this chemo-attraction idea, they mimicked cancer cell invasion in a specialized, dual compartment petri dish called a Boyden chamber. In the bottom compartment, they placed the liquid food, or media, that SVZ brain stem cells had been grown in. On the upper compartment, they placed the cancerous glioma cells. A porous, gelatin membrane between the two compartments acts as a barrier but allows the cells to receive signals from the lower compartment and migrate down into the media if a chemoattractant is present. And that’s what they saw: a significant glioma cell migration through the gelatin toward the brain stem cell media.

Boyden chamber assay. Image: Integr. Biol., 2009,1, 170-181

Pleiotrophin: an unintentional communicator with brain cancer cells
Something or somethings in the SVZ brain stem cell media had to be attracting the glioma cells. So, the Stanford team analyzed the composition of the media and identified four proteins that, when physically complexed together, had the same chemo-attraction ability as the media. They were pleased to find that one of the four proteins is pleiotrophin which is known to not only play a role in normal brain development and regeneration but also to increase glioma cell migration. And in this study, they showed that higher levels of pleiotrophin are present in the SVZ brain stem cell area compared to other regions of the brain. They went on to show that blocking the production of pleiotrophin in mice reduced the invasion of glioma cells into the SVZ region. This result suggests that blocking the release of pleiotrophin by brain stem cells in the SVZ could help prevent or slow down the spread of glioma in patients’ brains without the need of irradiating this important part of the brain.

The silver lining: hsp90 inhibitors have therapeutic promise

Michelle Monje, MD, PhD

To further explore this potential therapeutic approach, the team examined hsp90, one of the other three proteins complexed with pleiotrophin. Though it doesn’t have chemoattractant properties, it still is a necessary component and may act to stabilize pleiotrophin. It also turns out that inhibitors for hsp90 have already been developed in the clinic for treating various cancers. When the researchers in this study blocked hsp90 production in the SVZ region of mice, they observed a reduced invasion of glioma cells. Though clinical grade hsp90 inhibitors exist, team lead  Michelle Monje, MD, PhD – assistant professor of neurology, Stanford University – tells me that some tweaking of these drugs will be necessary to reach gliomas:

“Our challenge is to find an hsp90 inhibitor that penetrates the brain at effective concentrations.”

Once they find that inhibitor, it could provide new options, and hope, for people diagnosed with this dreadful cancer.

Treatments, cures and clinical trials: an in-person update on CIRM’s progress

Patients and Patient Advocates are at the heart of everything we do at CIRM. That’s why we are holding three free public events in the next few months focused on updating you on the stem cell research we are funding, and our plans for the future.

Right now we have 33 projects that we have funded in clinical trials. Those range from heart disease and stroke, to cancer, diabetes, ALS (Lou Gehrig’s disease), two different forms of vision loss, spinal cord injury and HIV/AIDS. We have also helped cure dozens of children battling deadly immune disorders. But as far as we are concerned we are only just getting started.

Over the course of the next few years, we have a goal of adding dozens more clinical trials to that list, and creating a pipeline of promising therapies for a wide range of diseases and disorders.

That’s why we are holding these free public events – something we try and do every year. We want to let you know what we are doing, what we are funding, how that research is progressing, and to get your thoughts on how we can improve, what else we can do to help meet the needs of the Patient Advocate community. Your voice is important in helping shape everything we do.

The first event is at the Gladstone Institutes in San Francisco on Wednesday, September 6th from noon till 1pm. The doors open at 11am for registration and a light lunch.

Gladstone Institutes

Here’s a link to an Eventbrite page that has all the information about the event, including how you can RSVP to let us know you are coming.

We are fortunate to be joined by two great scientists, and speakers – as well as being CIRM grantees-  from the Gladstone Institutes, Dr. Deepak Srivastava and Dr. Steve Finkbeiner.

Dr. Srivastava is working on regenerating heart muscle after it has been damaged. This research could not only help people recover from a heart attack, but the same principles might also enable us to regenerate other organs damaged by disease. Dr. Finkbeiner is a pioneer in diseases of the brain and has done ground breaking work in both Alzheimer’s and Huntington’s disease.

We have two other free public events coming up in October. The first is at UC Davis in Sacramento on October 10th (noon till 1pm) and the second at Cedars-Sinai in Los Angeles on October 30th (noon till 1pm). We will have more details on these events in the coming weeks.

We look forward to seeing you at one of these events and please feel free to share this information with anyone you think might be interested in attending.

Targeting hair follicle stem cells could be the key to fighting hair loss

Chia Pets make growing hair look easy. You might not be familiar with these chia plant terracotta figurines if you were born after the 80s, but I remember watching commercials growing up and desperately wanting a “Chia Pet, the pottery that grows!”

My parents eventually caved and got me a Chia teddy bear, and I was immediately impressed by how easy it was for my bear to grow “hair”. All I needed to do was to sprinkle water over the chia seeds and spread them over my chia pet, and in three weeks, voila, I had a bear that had sprouted a lush, thick coat of chia leaves.

These days, you can order Chia celebrities and even Chia politicians. If only treating hair loss in humans was as easy as growing sprouts on the top of Chia Mr. T’s head…

Activating Hair Follicle Stem Cells, the secret to hair growth?

That day might come sooner than we think thanks to a CIRM-funded study by UCLA scientists.

Published today in Nature Cell Biology, the UCLA team reported a new way to boost hair growth that could eventually translate into new treatments for hair loss. The study was spearheaded by senior authors Heather Christofk and William Lowry, both professors at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

Christofk and Lowry were interested in understanding the biology of hair follicle stem cells (HFSCs) and how their metabolism (the set of chemical changes required for a cell to sustain itself) plays a role in hair growth. HFSCs are adult stem cells that live in the hair follicles of our skin. They are typically inactive but can quickly “wake up” and actively divide when a new hair growth cycle is initiated. When HFSCs fail to activate, hair loss occurs.

A closer look at HFSCs in mice revealed that these stem cells are dependent on the products of the glycolytic pathway, a metabolic pathway that converts the nutrient glucose into a metabolite called pyruvate, to stimulate their activation. The HFSCs have a choice, they can either give the pyruvate to their mitochondria to produce more energy, or they can break down the pyruvate into another metabolite called lactate.

The scientists found that if they tipped the balance towards producing more lactate, the HFSCs activated and induced hair growth. On the other hand, if they blocked lactate production, HFSCs couldn’t activate and new hair growth was blocked.

In a UCLA news release, Lowry explained the novel findings of their study,

“Before this, no one knew that increasing or decreasing the lactate would have an effect on hair follicle stem cells. Once we saw how altering lactate production in the mice influenced hair growth, it led us to look for potential drugs that could be applied to the skin and have the same effect.”

New drugs for hair loss?

In the second half of the study, the UCLA team went on the hunt for drugs that promote lactate production in HFSCs in hopes of finding new treatment strategies to battle hair loss. They found two drugs that boosted lactate production when applied to the skin of mice. One was called RCGD423, which activates the JAK-Stat signaling pathway and stimulates lactate production. The other drug, UK5099, blocks the entry of pyruvate into the mitochondria, thereby forcing HFSCs to turn pyruvate into lactate resulting in hair growth. The use of both drugs for boosting hair growth are covered by provisional patent applications filed by the UCLA Technology Development Group.

Untreated mouse skin showing no hair growth (left) compared to mouse skin treated with the drug UK5099 (right) showing hair growth. Credit: UCLA Broad Stem Cell Center/Nature Cell Biology

Aimee Flores, the first author of the study, concluded by explaining why using drugs to target the HFSC metabolism is a promising approach for treating hair loss.

“Through this study, we gained a lot of interesting insight into new ways to activate stem cells. The idea of using drugs to stimulate hair growth through hair follicle stem cells is very promising given how many millions of people, both men and women, deal with hair loss. I think we’ve only just begun to understand the critical role metabolism plays in hair growth and stem cells in general; I’m looking forward to the potential application of these new findings for hair loss and beyond.”

If these hair growth drugs pan out, scientists might give Chia Pets a run for their money.

CIRM weekly stem cell roundup: minibrain model of childhood disease; new immune insights; patient throws out 1st pitch

New human Mini-brain model of devastating childhood disease.
The eradication of Aicardi-Goutieres Syndrome (AGS) can’t come soon enough. This rare but terrible inherited disease causes the immune system to attack the brain. The condition leads to microcephaly (an abnormal small head and brain size), muscle spasms, vision problems and joint stiffness during infancy. Death or a persistent comatose state is common by early childhood. There is no cure.

Though animal models that mimic AGS symptoms are helpful, they don’t reflect the human disease closely enough to provide researchers with a deeper understanding of the mechanisms of the disease. But CIRM-funded research published this week may be a game changer for opening up new therapeutic strategies for the children and their families that are suffering from AGS.

Organoid mini-brains are clusters of cultured cells self-organized into miniature replicas of organs. Image courtesy of Cleber A. Trujillo, UC San Diego.

To get a clearer human picture of the disease, Dr. Alysson Muotri of UC San Diego and his team generated AGS patient-derived induced pluripotent stem cells (iPSCs). These iPSCs were then grown into “mini-brains” in a lab dish. As described in Cell Stem Cell, their examination of the mini-brains revealed an excess of chromosomal DNA in the cells. This abnormal build up causes various toxic effects on the nerve cells in the mini-brains which, according to Muotri, had the hallmarks of AGS in patients:

“These models seemed to mirror the development and progression of AGS in a developing fetus,” said Muotri in a press release. “It was cell death and reduction when neural development should be rising.”

In turns out that the excess DNA wasn’t just a bunch of random sequences but instead most came from so-called LINE1 (L1) retroelements. These repetitive DNA sequences can “jump” in and out of DNA chromosomes and are thought to be remnants of ancient viruses in the human genome. And it turns out the cell death in the mini-brains was caused by the immune system’s anti-viral response to these L1 retroelements. First author Charles Thomas explained why researchers may have missed this in their mouse models:

“We uncovered a novel and fundamental mechanism, where chronic response to L1 elements can negatively impact human neurodevelopment. This mechanism seems human-specific. We don’t see this in the mouse.”

The team went on to test the anti-retroviral effects of HIV drugs on their AGS models. Sure enough, the drugs decreased the amount of L1 DNA and cell growth rebounded in the mini-brains. The beauty of using already approved drugs is that the route to clinical trials is much faster and in fact a European trial is currently underway.

For more details, watch this video interview with Dr. Muotri:

New findings about immune cell development may open door to new cancer treatments
For those of you who suffer with seasonal allergies, you can blame your sniffling and sneezing on an overreaction by mast cells. These white blood cells help jump start the immune system by releasing histamines which makes blood vessels leaky allowing other immune cells to join the battle to fight disease or infection. Certain harmless allergens like pollen are mistaken as dangerous and can also cause histamine release which triggers tearing and sneezing.

Mast cells in lab dish. Image: Wikipedia.

Dysfunction of mast cells are also involved in some blood cancers. And up until now, it was thought a protein called stem cell factor played the key role in the development of blood stem cells into mast cells. But research reported this week by researchers at Karolinska Institute and Uppsala University found cracks in that previous hypothesis. Their findings published in Blood could open the door to new cancer therapies.

The researchers examine the effects of the anticancer drug Glivec – which blocks the function of stem cell factor – on mast cells in patients with a form of leukemia. Although the number of mature mast cells were reduced by the drug, the number of progenitor mast cells were not. The progenitors are akin to teenagers in that they’re at an intermediate stage of development, more specialized than stem cells but not quite mast cells. The team went on to confirm that stem cell factor was not required for the mast cell progenitors to survive, multiply and mature. Instead, their work identified two other growth factors, interleukin 3 and 6, as important for mast cell development.

In a press release, lead author Joakim Dahlin, explained how these new insights could lead to new therapies:

“The study increases our understanding of how mast cells are formed and could be important in the development of new therapies, for example for mastocytosis for which treatment with imatinib/Glivec is not effective. One hypothesis that we will now test is whether interleukin 3 can be a new target in the treatment of mast cell-driven diseases.”

Patient in CIRM-funded trial regains use of arms, hands and fingers will throw 1st pitch in MLB game.
We end this week with some heart-warming news from Asterias Biotherapeutics. You avid Stem Cellar readers will remember our story about Lucas Lindner several weeks back. Lucas was paralyzed from the neck down after a terrible car accident. Shortly after the accident, in June of 2016, he enrolled in Asterias’ CIRM-funded trial testing an embryonic stem cell-based therapy to treat his injury. And this Sunday, August 13th, we’re excited to report that due to regaining the use of his arms, hands and fingers since the treatment, he will throw out the first pitch of a Major League Baseball game in Milwaukee. Congrats to Lucas!

For more about Lucas’ story, watch this video produced by Asterias Biotherapeutics:

High school students SPARK an interest in stem cell research

SPARK students at the 2017 Annual Meeting at the City of Hope.

High school is a transformative time for any student. It marks the transition from childhood to adulthood and requires discipline, dedication and determination to excel and get into their desired college or university.

The barrier to entry for college now seems much higher than when I was eighteen, but I am not worried for the current generation of high school students. That’s because I’ve met some of the brightest young minds this past week at the 2017 CIRM SPARK meeting.

SPARK is CIRM’s high school education program, which gives underprivileged students in California the opportunity to train as stem cell scientists for the summer. Students participate in a summer research internship at one of seven programs at leading research institutes in the state. They attend scientific lectures, receive training in basic lab techniques, and do an eight-week stem cell research project under the guidance of a mentor.

At the end of the summer, SPARK students congregate at the annual SPARK poster meeting where they present the fruits of their labor. Meeting these students in person is my favorite time of the year. Their enthusiasm for science and stem cell research is contagious. And when you engage them or listen to them talk about their project, it’s hard to remember that they are still teenagers and not graduate level scientists.

What impresses me most about these students is their communication skills. Each summer, I challenge SPARK students to share their summer research experience through social media and blogging, and each time they go above and beyond with their efforts. Training these students as effective science communicators is important to me. They are the next generation of talented scientists who can help humanize research for the public. They have the power to change the perception of science as a field to be embraced and one that should receive proper funding.

It’s also inspiring to me that this young generation can effectively educate their friends, family and the public about the importance of stem cell research and how it will help save the lives of patients who currently don’t have effective treatments. If you haven’t already, I highly recommend checking out the #CIRMSPARKlab hashtag on Instagram to get a taste of what this year’s group of students accomplished during their internships.

Asking students, many of whom are learning to do research for the first time, to post on Instagram once a week and write a blog about their internship is a tall task. And I believe with any good challenge, there should be a reward. Therefore, at this year’s SPARK meeting held at the City of Hope in Duarte, California, I handed out prizes.

It was very difficult to pick winners for our presentation, social media and blogging awards because honestly, all our students were excellent this year. Even Kevin McCormack, Director of CIRM’s Communications, who helped me read the students’ blogs said,

“This was really tough. The standard of the blogs this year was higher than ever; and previous years had already set the bar really high. It was really difficult deciding which were really good and which were really, really good.”

Ok, enough with the hype, I know you want to read these award-winning blogs so I’ve shared them below. I hope that they inspire you as much as they have inspired me.


Amira Hirara

Amira Hirara (Children’s Hospital Oakland Research Institute)

It was a day like any other. I walked into the room, just two minutes past 10:30am, ready for another adventurous day in the lab. Just as I settle down, I am greeted by my mentor with the most terrifying task I have ever been asked to perform, “Will you passage the cells for me…alone?” Sweat begins to pour down my cemented face as I consider what is at stake.

The procedure was possibly thirty steps long and I have only executed it twice, with the supervision of my mentor of course. To be asked to do the task without the accompaniment of an experienced individual was unthought-of. I feel my breath begin to shorten as I mutter the word “Ok”. Yet it wasn’t just the procedure that left me shaking like a featherless bird, it was the location of my expedition as well. The dreaded tissue culture room. If even a speck of dirt enters the circulating air of the biosafety cabinet, your cells are at risk of death…death! I’ll be a cell murderer. “Alright”, she said, “I’ll just take a look at the cells then you’ll be on your way.” As we walk down the hallway, my eyes began to twitch as I try to recall the first steps of the procedure. I remember freezing our plates with Poly-ornithine and laminin, which essentially simulates the extracellular environment and allows adhesion between the cell and the plate itself. I must first add antibiotics to rid the frozen plate of potential bacteria. Then I should remove my cells from the incubator, and replace the old solution with accutase and new media, to nourish the cells, as well as unbind them from the plate before. Passaging is necessary when the cell density gets too high, as the cells must be relocated to a roomier environment to better promote survival. As we approach the tissue culture room, my jaw unclenches, as I realize the whirlwind of ideas meant I know more than I thought. My mentor retrieves our cells, views them under the microscope, and deems them ‘ready for passaging’.

“Good luck Amira” she says to me with a reassuring smile. I enter the room ready for battle. Placing first my gloves and coat, I then spray my hands and all things placed in the cabinet with 70% ethanol, to insure a sterile work environment. Back to the procedure, I’ll place the cellular solution of accutase and media into a covalent tube. After, I’ll centrifuge it for two minutes until a cellular pellet forms at the bottom, then dissolve the cells in fresh media, check its density using a cell counter, and calculate the volume of cellular solution needed to add to my once frozen plates. Wait, once I do that, I’ll be all done. I eagerly execute all the steps, ensuring both accuracy and sterility in my work. Pride swells within me as I pipette my last milliliter of solution into my plate. The next day, my mentor and I stop by to check on how our sensitive neural stem cells are doing. “Wow Amira, I am impressed, your cells seem very confluent in their new home, great job!” I smile slyly and begin to nod my head. I now walk these hallways, with a puffed chest, brightened smile, and eagerness to learn. My stem cells did not die, and having the amazing opportunity to master their treatment and procedures, is something I can never forget.

 

Gaby Escobar

Gaby Escobar (Stanford University)

Walking into the lab that would become my home for the next 8 weeks, my mind was an empty canvas.  Up to that point, my perception of the realm of scientific research was one-sided. Limited to the monotonous textbook descriptions of experiments that were commonplace in a laboratory, I wanted more. I wanted to experience the alluring call of curiosity. I wanted to experience the flash of discovery and the unnerving drive that fueled our pursuit of the unknown. I was an empty canvas looking for its first artistic stroke.

Being part of the CIRM Research program, I was lucky enough to have been granted such opportunity. Through the patient guidance of my mentor, I was immersed into the limitless world of stem cell biology. From disease modeling to 3D bioprinting, I was in awe of the capabilities of the minds around me. The energy, the atmosphere, the drive all buzzed with an inimitable quest for understanding. It was all I had imagined and so, so much more.

However, what many people don’t realize is research is an arduous, painstaking process. Sample after sample day after day, frustration and doubt loomed above our heads as we tried to piece together a seemingly pieceless puzzle.  Inevitably, I faced the truth that science is not the picture-perfect realm I had imagined it to be. Rather, it is tiring, it is relentless, and it is unforgiving. But at the same time, it is incomparably gratifying. You see, the innumerable samples, the countless gels and PCRS, all those futile attempts to fruitlessly make sense of the insensible, have meaning. As we traversed through the rollercoaster ride of our project, my mentor shared a personal outlook that struck very deeply with me: her motivation to work against obstacle after obstacle comes not from the recognition or prestige of discovering the next big cure but rather from the notion that one day, her perseverance may transform someone’s life for the good.  And in that, I see the beauty of research and science: the coming together of minds and ideas and bewildering intuitions all for the greater good.

As I look back, words cannot express the gratitude I feel for the lessons I have learned. Undoubtedly, I have made countless mistakes (please don’t ask how many gels I’ve contaminated or pipettes I have dropped) but I’ve also created the most unforgettable of memories. Memories that I know I will cherish for the journey ahead of me. Having experienced the atmosphere of a vibrant scientific community, I have found a second home, a place that I can explore and question and thrive. And although not every day will hold the cure to end all diseases or hand an answer on a silver platter, every day is another opportunity.  And with that, I walk away perhaps not with the masterpiece of art that I had envisioned in my mind but rather with a burning spark of passion, ready to ignite.

 

Anh Vo

Ahn Vo (UC Davis)

With college selectivity increasing and acceptance rates plummeting, the competitive nature within every student is pushed to the limit. In high school, students are expected to pad up their resumes and most importantly, choose an academic path sooner rather than later. However, at 15, I felt too young to experience true passion for a field. As I tried to envision myself in the future, I wondered, would I be someone with the adrenaline and spirit of someone who wants to change the world or one with hollow ambitions, merely clinging onto a paycheck with each day passing? At the very least, I knew that I didn’t want to be the latter.

The unrelenting anxiety induced by the uncertainty of my own ambitions was intoxicating. As my high school career reached its halfway mark, I felt the caving pressure of having to choose an academic path.

“What do you want to be?” was one of the first questions that my mentor, Whitney Cary, asked me. When I didn’t have an answer, she assured me that I needed to keep my doors open, and the SPARK program was the necessary first step that I needed to take to discovering my passion.

As I reflected on my experience, the SPARK program was undoubtedly the “first step”. It was the first step into a lab and above all, into a community of scientists, who share a passion for research and a vehement resolve to contribute to scientific merit. It was the integration into a cohort of other high school students, whose brilliance and kindness allowed us to forge deeper bonds with each other that we will hold onto, even as we part ways. It was the first nervous step into the bay where I met the Stem Cell Core, a team, whose warm laughter and vibrancy felt contagious. Finally, it was the first uncertain stumble into the tissue culture room, where I conceived a curiosity for cell culture that made me never stop asking, “Why?”

With boundless patience, my mentor and the Stem Cell Core strove to teach me techniques, such as immunocytochemistry and continually took the time out of their busy day to reiterate concepts. Despite my initial blunders in the hood, I found myself in a place without judgement, and even after discouraging incidents, I felt a sense of consolation in the witty and good-humored banter among the Stem Cell Core. At the end of every day, the unerring encouragement from my mentor strengthened my resolve to continue improving and incited an earnest excitement in me for the new day ahead. From trembling hands, nearly tipping over culture plates and slippery gloves, overdoused in ethanol, I eventually became acquainted with daily cell culture, and most importantly, I gained confidence and pride in my work.

I am grateful to CIRM for granting me this experience that has ultimately cultivated my enthusiasm for science and for the opportunity to work alongside remarkable people, who have given me new perspectives and insights. I am especially thankful to my mentor, whose stories of her career journey have inspired me to face the future with newfound optimism in spite of adversity.

As my internship comes to a close, I know that I have taken my “first step”, and with a revived mental acquisitiveness, I eagerly begin to take my second.

Other 2017 SPARK Awards

Student Speakers: Candler Cusato (Cedars-Sinai), Joshua Ren (Stanford)

Instagram/Social Media: Jazmin Aizpuru (UCSF), Emily Beckman (CHORI), Emma Friedenberg (Cedars-Sinai)

Poster Presentations: Alexander Escudero (Stanford), Jamie Kim (CalTech), Hector Medrano (CalTech), Zina Patel (City of Hope)


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A funny thing happened on my way to a PhD: one scientists change of mind and change of direction

Laurel Barchas is an old and dear friend of the communications team here at CIRM. As a student at U.C. Berkeley she helped us draft our education portal – putting together a comprehensive curriculum to help high schools teach students about stem cells in a way that met all state and federal standards. But a funny thing happened on her way to her Ph.D., she realized she had changed her mind about research, and so she changed her career direction.  

Laurel recently wrote this blog about that experience for the new and improved website of the Student Society for Stem Cell Research (SSSCR) –

Laurel #1

Laurel Barchas at the World Stem Cell Summit 2013

Stem cell parental advice—you can grow up to be anything!

I was one of those students who, since high school, knew I was destined for the lab. Throughout some of high school, and all of college and graduate school, I had internships or positions in amazing labs that warmly took me in and trained me how to be a scientist. I loved designing and carrying out experiments on my stem cells, presenting at lab meetings, writing theses, and teaching others about my work through undergraduate lectures and high school presentations. My participation in the Student Society for Stem Cell Research hugely supported all of my efforts; it even enabled me to get one of my first jobs as a contract curriculum writer (a project manager role) with the California Institute for Regenerative Medicine, which launched my writing career.

Four years into my biology PhD program, things became clear that I didn’t want to do research anymore. I couldn’t handle the failure inherent in doing research. I wasn’t able to put in the time and focus necessary to do big experiments—then repeat them over and over. Although I loved science, I wasn’t meant to be a career scientist like many of my colleagues. I was a science communicator. Realizing this, and taking into account my personal struggles, my advisers and I decided the best thing was to get a terminal master’s degree.**

Differentiation—finding the right path

I struggled for a while finding a job that suited me. I worked as an education consultant, writing materials directed at teachers and students. I worked as a marketing, communications and operations assistant for a real estate group. I looked for jobs as a teacher, curriculum developer, and science education program coordinator, but none felt quite right for me. Although I had extensive experience in school developing materials for teachers and giving presentations to students, and I knew education could be a rewarding career path, I wasn’t sure I wanted to be in the academic world anymore.

Finally, I found some listings looking for technical writers. I didn’t even know what that was at the time. Various biotech companies had their feelers out for entry level writers with advanced degrees in biology or STEM fields—and a master’s degree was just fine. It turns out I was a perfect fit. Surprisingly, many people in the “tech com” (technical communications) and “mar com” (marketing communications) departments at my company had a similar experience; they didn’t want careers in research or the medical professions, so they chose communications.

Laurel #2

Life as a technical writer—feeling like a glial cell

As a technical writer at my company, I have many responsibilities beyond writing and editing user manuals, application notes, and diagrams. Tech writers are much like the oft-forgotten glial cells that “glue the brain together.” I manage each project from start to finish, and I get to work on all types of technical documentation and marketing collateral with a team of company scientists (R&D), graphic designers, marketing specialists, coders, product managers, and other writers. Often, I have major creative input on the content, design, and development of marketing campaigns. I enjoy starting with ideas—maybe a few bullet points or a rough draft—and building colorful, captivating content. It feels like solving a complex puzzle.

I’ve gotten the chance to write articles on human induced pluripotent stem cell-derived beta cells for a drug discovery publication and to create portals for our website. I’ve helped make booth panels and printed resources for conferences like the International Society for Stem Cell Research. Most importantly (to me), I’ve managed to stay within the field of stem cell research/regenerative medicine. I am the main writer for that product and service line, so I can use my expertise and experience (plus, knowledge of my audience) to present products that advance my audience’s basic, translational and clinical research.

I love my job. It pays well, has regular hours, and gives me a sense of belonging to a team. It’s fast paced, I’m working on a new thing every day, and I get to learn and write about the latest advancements from our R&D teams around the world. I could go on and on, but suffice it to say that the job fits like a glove, and I can see myself doing this long term. Also…I get to live in Silicon Valley! (Pros: great food, culture, people. Cons: cost of living, traffic.)

I hope you can get encouragement from the retelling of my experience that there is a space for you in this field. This is the first post in a series of articles about careers in regenerative medicine. I aim to take you through a tour of the vocational landscape—its ups, its downs—and am looking forward to hearing from you with any jobs/roles/scenarios you are curious about. Please comment on what you’d like to learn about next!

Remember: there are plenty of options and ways for you to apply your talent and experience to pushing our field forward. SSSCR is here to help!

*I want to thank everyone who serves in the research and medical areas. Without you our field would stop in its tracks. However, not everyone is cut out for such positions. Luckily, there are other options.

**Some reading this might say “awwwww, too bad, she was so close to that PhD” and some might say “that’s a major accomplishment and you can do a lot with that degree!” Both are right, but I choose to believe the latter, as I am so much happier now that I released myself from the allure of lab research and went into science communications. We tend to hold science and medicine up on pedestals; however, science communication facilitates almost all interactions between academic and industry scientists, clinicians, and the public. An understanding of and engagement with new science is critical to promoting a healthy democracy with citizens who can make informed decisions about their society’s future.

Laurel is a co-founder of SSSCR, the current Associate Director, and a member of the SSSCR International executive committee. She has been involved in SSSCR since 2004, when she helped start UC Berkeley’s chapter. Her main contributions are educating various communities about stem cell research and building career development opportunities for students. Along with a team of SSSCR members, Laurel created the California Institute for Regenerative Medicine’s stem cell education portal to provide teachers with the materials they need to engage students with the field. Currently, Laurel is a Senior Technical Writer focused on stem cell products and services.

How mice and zebrafish are unlocking clues to repairing damaged hearts

Bee-Gees

The Bee Gees, pioneers in trying to find ways to mend a broken heart. Photograph: Michael Ochs Archives

This may be the first time that the Australian pop group the Bee Gees have ever been featured in a blog about stem cell research, but in this case I think it’s appropriate. One of the Bee Gees biggest hits was “How can you mend a broken heart” and while it was a fine song, Barry and Robin Gibb (who wrote the song) never really came up with a viable answer.

Happily some researchers at the University of Southern California may succeed where Barry and Robin failed. In a study, published in the journal Nature Genetics, the USC team identify a gene that may help regenerate damaged heart tissue after a heart attack.

When babies are born they have a lot of a heart muscle cell called a mononuclear diploid cardiomyocyte or MNDCM for short. This cell type has powerful regenerative properties and so is able to rebuild heart muscle. However, as we get older we have less and less MNDCMs. By the time most of us are at an age where we are most likely to have a heart attack we are also most likely to have very few of these cells, and so have a limited ability to repair the damage.

Michaela Patterson, and her colleagues at USC, set out to find ways to change that. They found that in some adult mice less than 2 percent of their heart cells were MNDCMs, while other mice had a much higher percentage, around 10 percent. Not surprisingly the mice with the higher percentage of MNDCMs were better able to regenerate heart muscle after a heart attack or other injury.

So the USC team – with a little help from CIRM funding – dug a little deeper and did a genome-wide association study of these mice, that’s where they look at all the genetic variants in different individuals to see if they can spot common traits. They found one gene, Tnni3k, that seems to play a key role in generating MNDCMs.

Turning Tnni3K off in mice resulted in higher numbers of MNDCMs, increasing their ability to regenerate heart muscle. But when they activated Tnni3k in zebrafish it reduced the number of MNDCMs and impaired the fish’s ability to repair heart damage.

While it’s a long way from identifying something interesting in mice and zebrafish to seeing if it can be used to help people, Henry Sucov, the senior author on the study, says these findings represent an important first step in that direction:

“The activity of this gene, Tnni3k, can be modulated by small molecules, which could be developed into prescription drugs in the future. These small molecules could change the composition of the heart over time to contain more of these regenerative cells. This could improve the potential for regeneration in adult hearts, as a preventative strategy for those who may be at risk for heart failure.”

 

 

 

Stem cell stories that caught our eye: skin grafts fight diabetes, reprogramming the immune system, and Asterias expands spinal cord injury trial sites

Here are the stem cell stories that caught our eye this week.

Skin grafts fight diabetes and obesity.

An interesting new gene therapy strategy for fighting type 1 diabetes and obesity surfaced this week. Scientists from the University of Chicago made genetically engineered skin grafts that secrete a peptide hormone called glucagon-liked peptide-1 (GLP-1). This peptide is released by cells in the intestine and can lower blood sugar levels by stimulating pancreatic islet cells to secrete insulin (a hormone that promotes the absorption of glucose from the blood).

The study, which was published in the journal Cell Stem Cell, used CRISPR gene editing technology to introduce a mutation to the GLP-1 gene in mouse and human skin stem cells. This mutation stabilized the GLP-1 peptide, allowing it to hang around in the blood for longer. The team matured these stem cells into skin grafts that secreted the GLP-1 into the bloodstream of mice when treated with a drug called doxycycline.

When fed a high-fat diet, mice with a skin graft (left), genetically altered to secrete GLP-1 in response to the antibiotic doxycycline, gained less weight than normal mice (right). (Image source: Wu Laboratory, the University of Chicago)

On a normal diet, mice that received the skin graft saw a rise in their insulin levels and a decrease in their blood glucose levels, proving that the gene therapy was working. On a high fat diet, mice with the skin graft became obese, but when they were treated with doxycycline, GLP-1 secreted from their grafts reduced the amount of weight gain. So not only does their engineered skin graft technology look like a promising new strategy to treat type 1 diabetes patients, it also could be used to control obesity. The beauty of the technology is in its simplicity.

An article in Genetic Engineering and Biotechnology News that covered this research explained that Xiaoyang Wu, the senior author on the study, and his team “worked with skin because it is a large organ and easily accessible. The cells multiply quickly and are easily transplanted. And, transplanted cells can be removed, if needed. “Skin is such a beautiful system,” Wu says, noting that its features make it a perfect medium for testing gene therapies.”

Wu concluded that, “This kind of therapy could be potentially effective for many metabolic disorders.” According to GenBio, Wu’s team “is now testing the gene-therapy technique in combination with other medications.” They also hope that a similar strategy could be used to treat patients that can’t make certain proteins like in the blood clotting disorder hemophilia.

How to reprogram your immune system (Kevin McCormack)

When your immune system goes wrong it can cause all manner of problems, from type 1 diabetes to multiple sclerosis and cancer. That’s because an overactive immune system causes the body to attack its own tissues, while an underactive one leaves the body vulnerable to outside threats such as viruses. That’s why scientists have long sought ways to correct those immune dysfunctions.

Now researchers at the Gladstone Institutes in San Francisco think they have found a way to reprogram specific cells in the immune system and restore a sense of health and balance to the body. Their findings are published in the journal Nature.

The researchers identified a drug that targets effector T cells, which get our immune system to defend us against outside threats, and turns them into regulatory T cells, which control our immune system and stops it from attacking our own body.

Why would turning one kind of T cell into another be helpful? Well, in some autoimmune diseases, the effector T cells become overly active and attack healthy tissues and organs, damaging and even destroying them. By converting them to regulatory T cells you can prevent that happening.

In addition, some cancers can hijack regulatory T cells and suppress the immune system, allowing the disease to spread. By turning those cells into effector T cells, you can boost the immune system and give it the strength to fight back and, hopefully, kill the cancer.

In a news release, Gladstone Senior Investigator Sheng Ding, the lead scientists on the study, said their findings could have several applications:

“Our findings could have a significant impact on the treatment of autoimmune diseases, as well as on stem cell and immuno-oncology therapies.” 

Gladstone scientists Sheng Ding (right) and Tao Xu (left) discovered how to reprogram cells in our immune system. (Gladstone Institutes)

CIRM-funded spinal cord injury trial expands clinical sites

We have another update from CIRM’s clinical trial front. Asterias Biotherapeutics, which is testing a stem cell treatment for complete cervical (neck) spinal cord injury, is expanding its clinical sites for its CIRM-funded SCiStar Phase 1/2a trial. The company is currently treating patients at six sites in the US, and will be expanding to include two additional sites at Thomas Jefferson University Hospital in Philadelphia and the UC San Diego Medical Center, which is part of the UCSD Health CIRM Alpha Stem Cell Clinic.

In a company news release, Ed Wirth, Chief Medical Officer of Asterias said,

Ed Wirth

“We are excited about the clinical site openings at Thomas Jefferson University Hospital and UC San Diego Health. These sites provide additional geographical reach and previous experience with spinal cord injury trials to our SCiStar study. We have recently reported completion of enrollment in four out of five cohorts in our SCiStar study so we hope these institutions will also participate in a future, larger study of AST-OPC1.”

The news release also gave a recap of the trial’s positive (but still preliminary) results this year and their plans for completing trial enrollment.

“In June 2017, Asterias reported 9 month data from the AIS-A 10 million cell cohort that showed improvements in arm, hand and finger function observed at 3-months and 6-months following administration of AST-OPC1 were confirmed and in some patients further increased at 9-months. The company intends to complete enrollment of the entire SCiStar study later this year, with multiple safety and efficacy readouts anticipated during the remainder of 2017 and 2018.”

Scientists fix heart disease mutation in human embryos using CRISPR

Last week the scientific community was buzzing with the news that US scientists had genetically modified human embryos using CRISPR gene editing technology. While the story broke before the research was published, many journalists and news outlets weighed in on the study’s findings and the ethical implications they raise. We covered this initial burst of news in last week’s stem cell stories that caught our eye.

Shoukhrat Mitalipov (Leah Nash, New York Times)

After a week of suspense, the highly-anticipated study was published yesterday in the journal Nature. The work was led by senior author Dr. Shoukhrat Mitalipov from Oregon Health and Sciences University (and a member of CIRM’s Grants Working Group, the panel of experts who review applications to us for funding) in collaboration with scientists from the Salk Institute and Korea’s Institute for Basic Science.

In brief, the study revealed that the teams’ CRISPR technology could correct a genetic mutation that causes a disease called hypertrophic cardiomyopathy (HCM) in 72% of human embryos without causing off-target effects, which are unwanted genome modifications caused by CRISPR. These findings are a big improvement over previous studies by other groups that had issues with off-target effects and mosaicism, where CRISPR only correctly modifies mutations in some but not all cells in an embryo.

Newly fertilized eggs before gene editing, left, and embryos after gene editing and a few rounds of cell division. (Image from Shoukrat Mitalipov in New York Times)

Mitalipov spoke to STATnews about a particularly interesting discovery that he and the other scientists made in the Nature study,

“The main finding is that the CRISPR’d embryos did not accept the “repair DNA” that the scientists expected them to use as a replacement for the mutated gene deleted by CRISPR, which the embryos inherited from their father. Instead, the embryos used the mother’s version of the gene, called the homologue.”

Sharon Begley, the author of the STATnews article, argued that this discovery means that “designer babies” aren’t just around the corner.

“If embryos resist taking up synthetic DNA after CRISPR has deleted an unwanted gene, then “designer babies,” created by inserting a gene for a desirable trait into an embryo, will likely be more difficult than expected.”

Ed Yong from the Atlantic also took a similar stance towards Mitalipov’s study in his article titled “The Designer Baby Era is Not Upon Us”. He wrote,

“The bigger worry is that gene-editing could be used to make people stronger, smarter, or taller, paving the way for a new eugenics, and widening the already substantial gaps between the wealthy and poor. But many geneticists believe that such a future is fundamentally unlikely because complex traits like height and intelligence are the work of hundreds or thousands of genes, each of which have a tiny effect. The prospect of editing them all is implausible. And since genes are so thoroughly interconnected, it may be impossible to edit one particular trait without also affecting many others.”

Dr. Juan Carlos Izpisua Belmonte, who’s a corresponding author on the paper and a former CIRM grantee from the Salk Institute, commented on the impact that this research could have on human health in a Salk news release.

Co-authors Juan Carlos Izpisua Belmonte and Jun Wu. (Salk Institute)

“Thanks to advances in stem cell technologies and gene editing, we are finally starting to address disease-causing mutations that impact potentially millions of people. Gene editing is still in its infancy so even though this preliminary effort was found to be safe and effective, it is crucial that we continue to proceed with the utmost caution, paying the highest attention to ethical considerations.”

Pam Belluck from The New York Times also suggested that this research could have a significant impact on how we prevent disease in newborns.

“This research marks a major milestone and, while a long way from clinical use, it raises the prospect that gene editing may one day protect babies from a variety of hereditary conditions.”

So when will the dawn of CRISPR babies arrive? Ed Yong took a stab at answering this million dollar question with help from experts in the field.

“Not for a while. The technique would need to be refined, tested on non-human primates, and shown to be safe. “The safety studies would likely take 10 to 15 years before FDA or other regulators would even consider allowing clinical trials,” wrote bioethicist Hank Greely in a piece for Scientific American. “The Mitalipov research could mean that moment is 9 years and 10 months away instead of 10 years, but it is not close.” In the meantime, Mitalipov’s colleague Sanjiv Kaul says, “We’ll get the method to perfection so that when it’s possible to use it in a clinical trial, we can.”