Author: Katie Sharify

Two common viruses could trigger Alzheimer’s disease

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Researchers from Tufts University and the University of Oxford have found that two common viruses —the varicella zoster and herpes simplex viruses— could trigger Alzheimer’s disease.

Varicella zoster (VZV) is an extremely common virus causes which causes chickenpox. Once cured of the first infection, the virus tends to linger in peripheral nerves where they remain dormant. When these dormant viruses are reactivated, they cause shingles.

HSV-1, the subtype of the herpes simplex virus, causes both oral and genital herpes. It is a very common infection, affecting nearly 4 million people worldwide under the age of 50 years. The American Sexual Health Organization estimates that around one in two adults has oral herpes in the United States. 

Cytokines are produced in response to VZV. Cytokines are part of a healthy immune system. These small proteins help control the growth and activity of your blood cells and immune cells. Cytokines tell your immune system to do its job. But when too many cytokines are released, it can cause your immune system to go into overdrive, resulting in cytokine storm.

In their findings, published in the Journal of Alzheimer’s Disease, researchers found that when VZV infect neurons, they trigger an inflammatory response due to this overproduction of cytokines. This inflammatory response in turn awakens the herpes simplex viruses which typically lie dormant and harmless in the brain. With both viruses now active, inflammation throughout the brain is aggravated, potentially leading to the formation of plaque and the slow deterioration of neurons—both hallmarks of Alzheimer’s.

The study’s leading author, Dana Cairns, along with her team of collaborators gathered data by using lab grown cultures of brain nerve, or neural, stem cells. They found that infecting neurons with varicella zoster alone was not enough to trigger Alzheimer-like properties. However, when the herpes simplex was already lying-in wait, varicella zoster initiated a series of events that resulted in plaques, tangled fibers and brain damage.

“It’s a one-two punch of two viruses that are very common and usually harmless, but the lab studies suggest that if a new exposure to VZV wakes up dormant HSV-1, they could cause trouble,” explains Cairns. One of her collaborators, Oxford’s Ruth Itzhaki, was one of the first scientists to suggest a link between herpes infections and Alzheimer’s.

The California Institute for Regenerative Medicine (CIRM) has already invested almost $35 million in 21 different Alzheimer’s projects. In addition, we are committed to investing at least $1.5 billion in treatments that target conditions affecting the brain and central nervous system (CNS), including Alzheimer’s. 

An experimental gene therapy with a hairy twist

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In October 2019, 20-year-old Jordan Janz became the first person in the world to receive an experimental therapy for cystinosis. Cystinosis is a rare genetic disorder characterized by the accumulation of an amino acid called cystine in different tissues and organs of the body including the kidneys, eyes, muscles, liver, pancreas, and brain. This accumulation of cystine ultimately leads to multi-organ failure, eventually causing premature death in early adulthood. On average, cystinosis patients live to 28.5 years old. By that calculation, Janz didn’t have a lot of time.

The treatment was grueling but worth it. The experimental gene therapy –funded by the California Institute for Regenerative Medicine– seemed to work and Janz began to feel better. There was, however, an unexpected change. Janz’s almost white, blonde hair had settled into a darker tone. Of all the things the gene therapy was expected to alter –such as the severity of his cystinosis symptoms– hair color was not one of them. Eventually, the same phenomenon played out in other people: So far in the gene-therapy trial, four of the five patients –all of whom are white– have gotten darker hair.

The outcome, while surprising to researchers, didn’t seem to be a sign of something going awry, instead they determined that it might be a very visible sign of the gene therapy working.

The sudden hair-color changes were surprising to Stephanie Cherqui, a stem-cell scientist at UC San Diego and the principal investigator of the gene-therapy trial. However, it didn’t seem to be a sign of something going awry, instead Cherqui and her colleagues determined that it might be a very visible sign of the gene therapy working.

But exactly how did genetically modifying Janz’s (and other participants’) blood cells change his hair color? In this instance, scientists chose to genetically tweak blood stem cells because they have a special ability: Some eventually become white blood cells, which then travel to all different parts of the body.

Janz’s new white blood cells were genetically modified to express the gene that is mutated in cystinosis, called CTNS. Once they traveled to his eyes, skin, and gut, the white blood cells began pumping out the missing protein encoded by the gene. Cells in the area began taking up the protein and clearing away long accumulated cystine crystals. In Janz, the anti-cystine proteins from his modified blood cells must have reached the hair follicles in his skin. There, they cleared out the excess cystine that was blocking normal melanin production, and his hair got darker.

Hair color is one way in which patients in the clinical trial are teaching scientists about the full scope of the CTNS gene. The investigators have since added hair biopsies to the trial in order to track the color changes in a more systematic fashion.

Read the full article on The Atlantic.

Stem cells explained in different languages

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Science is hard. Explaining complex science to non-scientists is SUPER hard. But explaining science to non-native English speakers presents a whole new set of challenges.  

I would know. I’m a first-generation immigrant whose highly-educated parents arrived in their new home—the United States—a tad too late to become fluent in its native tongue. I’ve also had the unique experience of participating in a clinical trial using stem cells—a topic which my family still has trouble grasping.  

I still remember the day of my accident, which left me paralyzed from the chest down. My mother came into my room to cheerfully tell me that there was “something” that would “help me walk” again. Those “something” were human embryonic stem cells. The “help me walk” part was doctors simply explaining the potential of the treatment. In her frazzled mind, she could hardly understand Farsi, much less English. Being told that I was a candidate to participate in a stem cell trial somehow translated into being cured.

And she kept looking for the magic bullet. Countless internet searches revealed all sorts of clinics and wellness centers that offered a cure to just about any disease imaginable. My mom wondered, “Were these the same stem cells from my daughter’s trial? Maybe they are even better since they are curing so many folks!”

I tried my best to explain but there was always something missing in translation. I found that troubling. The language barrier made it so difficult to make informed decisions. I couldn’t imagine being a non-native English speaker and learning about such a complicated matter in a language I hadn’t yet mastered.

After all, stem cells are a topic that concerns the people of the world, not just certain countries or certain people speaking only in certain languages.

Dr. Paul Knoepfler would know. And not just because the statement comes straight from him. Paul is a stem cell scientist at UC Davis (full disclosure, we have funded some of his work). His blog, The Niche, is one of the longest-running blogs about regenerative medicine and an especially great resource for those without a science background.

More importantly, in 2021 Dr. Knoepfler launched SCOPE, an outreach effort to make available on the internet a basic page of facts about stem cells in as many languages as possible. What started with “Stem Cells in Spanish” has quickly transformed into a stem cell white paper now available in 35 different languages!

Naturally, I wasted no time and sent the Farsi version to my parents and the French one to my francophone mother-in-law. And it isn’t just me who is finding this information useful. Dr. Knoepfler says, “SCOPE has been a big hit and as the number of languages has grown, the number of page views of my white paper ‘What are stem cells?’ in languages besides English has skyrocketed. For example, just our Stem Cells in Spanish page has received over 680,000 views as of the first half of 2021, while our Indonesian page has over 300,000 views and our Arabic page has a quarter of a million. We are getting readers from all over the world who appreciate reading about stem cells in their own languages.”

To learn more about this initiative, visit Dr. Knoepfler’s blog.

IBSC directors bring in nearly $12 million to fund the future of bimolecular research at UC Santa Cruz

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Left to right: Lindsay Hinck and Camilla Forsberg

UC Santa Cruz professors Camilla Forsberg and Lindsay Hinck are not only pushing boundaries in their field as the female-led program directors of the Institute for the Biology of Stem Cells (IBSC), they’ve also been looking for ways to enhance the environment within the academic research infrastructure.

“We really wanted to make an effort to elevate everyone’s capacity for doing more research,” explains Forsberg. It was this drive that led the researchers to focus on bringing in grants to support students at different stages of their education to participate in research training programs.

So far, Fosberg and Hinck’s efforts have provided nearly $12 million in extramural funding for predoctoral and undergraduate training programs. The California Institute for Regenerative Medicine (CIRM), which provides graduate and postdoctoral funding, is one of the five funding institutions that have supported IBSC. This funding will shape the future of the IBSC, which brings together more than 30 laboratories across the Engineering and Physical and Biological Sciences divisions, as well as the Science & Justice Research Center.

“We didn’t set out to have five training programs, but then there were more opportunities, so we kept pitching our basic mentoring philosophies to different funders,” Forsberg said. “Now we have five different programs. I guess we found a secret sauce that made our funders excited.”

Forsberg and Hinck’s secret sauce is perhaps in part due to their devotion to forming strong peer connections amongst a group of talented graduate and postdoctoral researchers. The programs aim to connect cohorts of trainees who can interact and network through the IBSC in order to form a peer support ecosystem.

Additionally, IBSC strives to build cohorts that welcome and foster diverse perspectives as they will host an upcoming pilot program that aims to demystify the lengthy path from academia to a research career.

With their lastest $1 million training grant from the National Institute of Child Health and Human Development (NICHD), Forsberg and Hinck hope to provide support for postdoctoral scholars interested in the biotech industry. So far, biotech companies Jasper Therapeutics and Roche have joined the collaborative effort with IBSC to create shadowing opportunities for trainees to learn outside of the academic environment.

Furthermore, pre and postdoctoral trainees supported by these training grants can be hosted by several labs in the IBSC and beyond.

“The key thing about all these training programs is that they implement new ideas about structured graduate and postdoctoral training,” Hinck said. “While getting a training grant position is competitive, we try to make the structured training provided by the grants widely available so that all graduate students and postdoctoral scholars at UCSC can increase their skill sets. The environment that’s built around these training programs elevates opportunities for everyone.”

Read the full release here.

Celebrating National DNA Day Together

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DNA provides the code of life for nearly all living organisms. So, it’s no wonder that scientists have been studying DNA and the human genome (complete set of DNA) for decades.

In April 1953, James Watson and Francis Crick, in collaboration with Rosalind Franklin, first described the structure of DNA as a double helix. In April 2003, exactly 50 years later, scientists completed the Human Genome Project- a massive research effort to sequence and map all the genes that comprise the human genome.

That same year, Congress approved the first National DNA Day to commemorate both the discovery of the double helix and the completion of the Human Genome Project. The goal of National DNA Day is to offer students, educators, and the public an opportunity to learn about the DNA molecule and genomic research.

You can celebrate National DNA Day this year by following scientists Lilly Lee and Tom Quinn at Takara Bio as they demonstrate how to extract DNA from strawberries. Their lesson plan guides mentors to teach about DNA and genomic research, starting with having students extract DNA on their own.

Laurel Barchas, one of the people behind the video has also played an important role at the California Institute for Regenerative Medicine (CIRM). She has collaborated with us on many projects over the years, including helping us build CIRM’s own education portal with lessons for high school students that meet Next Generation Science Standards.

Watch the video below and Click Here for the full lesson plan!

Recovery from muscle loss injuries hindered by immune cell conflicts

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During a game in 2018, Alex Smith suffered a compound fracture that broke both the tibia and fibula in his right leg. The gruesome injury aside, the former 49ers quarterback soon developed life-threatening necrotizing fasciitis — a rare bacterial infection — that resulted in sepsis and required him to undergo 17 surgeries.

In a battle to save his life and avoid amputating his leg, doctors had to remove a great deal of his muscle tissue leading to volumetric muscle loss (VML). When Smith returned to the field after nearly two years of recovery, many called his comeback a “miracle”. 

Skeletal muscle is one of the most dynamic tissues of the human body. It defines how we move and can repair itself after injury using stem cells. However, when significant chunks of muscle are destroyed through severe injury (e.g. gunshot wound) or excessive surgery (like that of Smith’s), VML overwhelms the regenerative capacity of the muscle stem cells.

Despite the prevalence of these injuries, no standardized evaluation protocol exists for the characterization and quantification of VML and little is understood about why it consistently overwhelms the body’s natural regenerative processes. Current treatment options include functional free muscle transfer and the use of advanced bracing designs.

However, new research from the University of Michigan (U-M) may have just discovered why tissues often fail to regenerate from traumatic muscle loss injuries.

When researchers from U-M collaborated with partners at Georgia Tech, Emory University and the University of Oregon to study VML injuries in mice, they found that that sometimes post-injury immune cells become dysregulated and prevent stem cell repair. In VML injuries that don’t heal, neutrophils — a type of white blood cell — remain at the injured site longer than normal meaning that they’re not doing their job properly.

In addition, researchers found that intercellular communication between neutrophils and natural killers cells impacted muscle stem cell-mediated repair. When neutrophils communicated with natural killer cells, they were essentially prompted to self-destruct.

The findings suggest that by altering how the two cell types communicate, different healing outcomes may be possible and could offer new treatment strategies that eventually restore function and prevent limb loss. The team of researchers hope that better treatments could mean that recovery from VML injuries is no longer considered a “miracle”.

To read the source release, click here.

Stem cell-derived retinal patch continues to show promising results two years post-implantation

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Earlier this year we wrote about the promising results of a phase 1 clinical trial aimed at replacing the deteriorating cells in the retinas of people suffering from age-related macular degeneration- one of the leading causes of blindness worldwide for people over 50. Now there’s even more good news! Highlighted in a news story on the UC Santa Barbara (UCSB) website, researchers are continuing to make progress in their bid to secure approval from the Food and Drug Administration for the life-changing treatment.

Through the collaborative efforts of researchers at UCSB, University of Southern California and California Institute of Technology, a stem cell-derived implant using cells from a healthy donor was developed. The bioengineered implant, described as a scaffold, was then implanted under the retina of 16 participants. If the implant was to work, the new cells would then take up the functions of the old ones, and slow down or prevent further deterioration. In the best-case scenario, they could restore some lost vision.

The first sets of trials, funded by the California Institute for Regenerative Medicine (CIRM), concentrated on establishing the safety of the patch and collecting data on its effectiveness. Parting ways with old practices, the participants in the trial were given just two months of immunosuppressants whereas in the past, using donor cells meant that patients often had to be given long-term immunosuppression to stop their body’s immune system attacking and destroying the implanted cells. The team found that after two years, the presence of the patch hadn’t triggered other conditions associated with implantation, such as the formation of new blood vessels or scar tissue that could cause a detachment of the retina.

Even more importantly, they found no sign of inflammation that indicated an immune response to the foreign cells even after the patient was taken off immunosuppressants two months post-implantation. “What really makes us excited is that there is some strong evidence to show that the cells are still there two years after implantation and they’re still functional,” said Mohamed Faynus, a graduate student researcher in the lab of stem cell biologist Dennis O. Clegg at UCSB.

Having passed the initial phase, the team of researchers now hopes to begin phase 2 of the trial. This time, they are aiming to more specifically assesses the effectiveness of the patch in participants. Looking even farther ahead, the Clegg Lab and colleagues are also exploring combining multiple cell types on the patch to treat patients at varying stages of the disease.

In addition, there have also been improvements made to extend the shelf life of the patch. “Cryopreservation of the therapy significantly extends the product’s shelf-life and allows us to ship the implant on demand all over the world, thus making it more accessible to patients across the globe,” said Britney Pennington, a research scientist in the Clegg Lab.

Rare Disease: An Uphill Battle for Diagnosis and Treatment

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From left to right: Baby Dalia pre-diagnosis, Dalia on her way to the kindergarten, and Dalia today.

When Dalia was 5 years old, she was finally diagnosed with MERRF syndrome– an extremely rare form of mitochondrial disease. By then, her parents had been searching for an answer for three frustrating years. And like most parents of a child suffering from an undiagnosed medical condition, they expected that Dalia’s diagnosis would start a path to recovery. 

Unfortunately for Dalia and millions of Americans who have a rare disease, the condition is chronic and life-threating. More than 90% of rare diseases have no treatment. None are curable. Even more heartbreaking for Dalia’s family, MERRF is degenerative. Time is of essence.

According to research published in The Journal of Rare Disorders, it takes seeing 7.3 physicians and trying for 4.8 years before getting an accurate rare disease diagnosis. This uphill battle aside, diagnosis is merely the first challenge. For the 7,000 known rare diseases, less than 600 have FDA-approved treatments.  

The irony of rare diseases is that a lot of people have them. The total number of Americans living with a rare disease is estimated at between 25-30 million. Two-thirds of these patients are children. “You feel alone, because by definition, your child’s diagnosis is exceptional. And yet, 1 in 10 Americans and 300 million people globally are living with a rare disease,” explains Jessica Fein, Dalia’s mother, in a heartfelt HuffPost article detailing her daughter’s diagnostic odyssey. 

For decades, the rare disease community has pointed to these staggering numbers to highlight that while individual diseases may be rare, the total number of people with a rare disease is large. 

In 1983, Congress passed the Orphan Drug Act in order to provide incentives for drug companies to develop treatments for rare diseases. Between 1973 and 1983, fewer than 10 treatments for rare diseases were approved. Since 1983, hundreds of drugs and biologic products for rare diseases have been approved by the FDA. While researchers have made progress in learning how to diagnose, treat, and even prevent a variety of rare diseases, there is still much to do because like Dalia, most patients living with a rare disorder have no treatments to even consider. 

Four years after her diagnosis, Dalia lost her ability to walk, talk, eat, and breathe without a ventilator. At the time she was only 9 years old. More than a decade after her diagnosis, Dalia is finally enrolled in a clinical trial. Her parents hope that awareness about rare diseases and their prevalence will lead to research, funding, advocacy and health equity. 

Here at the California Institute for Regenerative Medicine (CIRM), we understand the importance of funding research that impacts not just the most common diseases. In fact, more than one third of all the projects we fund target a rare disease or condition such as: Retinitis pigmentosa, Sickle cell disease, Huntington’s disease, and Duchenne Muscular Dystrophy.

“[If] each of us learned a bit about just one rare disease… it probably wouldn’t change the trajectory for most of the people who are currently suffering, but it might help someone be diagnosed earlier. We’ve made leaps and bounds with awareness, research and treatment for AIDS, cancer and depression, all diseases that were once unknown… Awareness and action aren’t things that can be put on the back burner until more common illnesses are cured. We must do what we can today- and every day moving forward.”

First Patient Dosed in Phase 1 Clinical Trial for T1D

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There’s some good news for a company and a therapeutic approach that CIRM has been supporting for many years.

In September 2018, CRISPR Theraputics and ViaCyte entered a partnership to discover, develop and market gene-edited stem cell-derived therapies to treat type 1 diabetes (T1D). Today, they may stand one step closer to their goal. 

Last week the companies jointly announced that they have dosed the first subject in the Phase 1 clinical trial of VCTX210 for the treatment of T1D. VCTX210 is an investigational stem cell-based therapy. It was developed combining CRISPR’s gene-editing technology with ViaCyte’s stem cell expertise to generate pancreatic beta cells that can evade the immune system.

ViaCyte, a regenerative medicine company long backed by CIRM, has developed an implantable device which contains pancreatic endoderm cells that mature over a few months and turn into insulin-producing pancreatic islet cells, the kind destroyed by T1D. 

ViaCyte’s implantable stem cell pouch

Using CRISPR technology, the genetic code of the implanted cells is modified to create beta cells that avoid all recognition by the immune system. This collaboration aims to eliminate the requirement of patients taking daily immunosuppressants to stop the immune system from attacking the implanted cells. 

The first phase of the VCTX210 clinical trial will assess the safety, tolerability, and immune evasion in patients with T1D. 

“We are excited to work with CRISPR Therapeutics and ViaCyte to carry out this historic, first-in-human transplant of gene-edited, stem cell-derived pancreatic cells for the treatment of diabetes designed to eliminate the need for immune suppression,” said James Shapiro, a clinical investigator in the trial. “If this approach is successful, it will be a transformative treatment for patients with all insulin-requiring forms of diabetes.”

CIRM has been a big investor in ViaCyte’s work for many years and has invested more than $72 million in nine different awards.  

Educating and training the next generation of regenerative science workforce

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Bridges scholars presenting their research posters to CIRM team members and other scientists

Regenerative medicine is a diverse and rapidly evolving field, employing core expertise from biologists, engineers, and clinicians. As the field continues to advance, a well-trained regenerative science workforce is needed to apply the newest discoveries to clinical care. That’s why one of the goals outlined in our new 5-year Strategic Plan is to build a diverse and highly skilled workforce to support the growing regenerative medicine economy in California.  

Since its inception, the California Institute for Regenerative Medicine (CIRM) has been committed to educating the next generation of researchers, leaders, and innovators. Through its existing educational pillar programs such as SPARK and Bridges, the agency has been able to provide unique training and career development opportunities to a wide range of students from high school to college and beyond.

Through our new Strategic Plan, CIRM hopes to enhance training and education of the future California workforce by making it easier for students to start their career, accelerate career advancement, and provide greater access for diverse and underrepresented groups. Training and educating individuals who come from varied backgrounds brings new perspectives and different skillsets which enhance the development of the entire field, from basic and clinical research to manufacturing and commercialization.

The workforce training programs will be combined with CIRM’s other pillar programs to facilitate career entry at multiple levels. Through connecting the existing EDUC pillar programs with the planned California Manufacturing Network infrastructure program, CIRM hopes to address the critical need for a highly trained manufacturing workforce. By leveraging the Alpha Clinics and Community Care Centers, the agency will work to develop education curricula that address the currently unmet need for Clinical Research Coordinators. CIRM’s competency hubs and knowledge networks will also incorporate education and training programs to provide career pathways in emerging technologies, computational biology and data sciences.

You can read more about these goals in our 2022-27 Strategic Plan.