A word from our Chair, several in fact

In 2005, the New Oxford American Dictionary named “podcast” its word of the year. At the time a podcast was something many had heard of but not that many actually tuned in to. My how times have changed. Now there are some two million podcasts to chose from, at least according to the New York Times, and who am I to question them.

Yesterday, in the same New York Times, TV writer Margaret Lyons, wrote about how the pandemic helped turn her from TV to podcasts: “Much in the way I grew to prefer an old-fashioned phone call to a video chat, podcasts, not television, became my go-to medium in quarantine. With their shorter lead times and intimate production values, they felt more immediate and more relevant than ever before.”

I mention this because an old colleague of ours at CIRM, Neil Littman, has just launched his own podcast and the first guest on it was Jonathan Thomas, Chair of the CIRM Board. Their conversation ranged from CIRM’s past to the future of the regenerative field as a whole, with a few interesting diversions along the way. It’s fun listening. And as Margaret Lyons said it might be more immediate and more relevant than ever before.

Charting a course for the future

A new home for stem cell research?

Have you ever been at a party where someone says “hey, I’ve got a good idea” and then before you know it everyone in the room is adding to it with ideas and suggestions of their own and suddenly you find yourself with 27 pages of notes, all of them really great ideas. No, me neither. At least, not until yesterday when we held the first meeting of our Scientific Strategy Advisory Panel.

This is a group that was set up as part of Proposition 14, the ballot initiative that refunded CIRM last November (thanks again everyone who voted for that). The idea was to create a panel of world class scientists and regulatory experts to help guide and advise our Board on how to advance our mission. It’s a pretty impressive group too. You can see who is on the SSAP here.  

The meeting involved some CIRM grantees talking a little about their work but mostly highlighting problems or obstacles they considered key issues for the future of the field as a whole. And that’s where the ideas and suggestions really started flowing hard and fast.

It started out innocently enough with Dr. Amander Clark of UCLA talking about some of the needs for Discovery or basic research. She advocated for a consortium approach (this quickly became a theme for many other experts) with researchers collaborating and sharing data and findings to help move the field along.

She also called for greater diversity in research, including collecting diverse cell samples at the basic research level, so that if a program advanced to later stages the findings would be relevant to a wide cross section of society rather than just a narrow group.

Dr. Clark also said that as well as supporting research into neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, there needed to be a greater emphasis on neurological conditions such as autism, bipolar disorder and other mental health problems.

(CIRM is already committed to both increasing diversity at all levels of research and expanding mental health research so this was welcome confirmation we are on the right track).

Dr. Mike McCun called for CIRM to take a leadership role in funding fetal tissue research, things the federal government can’t or won’t support, saying this could really help in developing an understanding of prenatal diseases.

Dr. Christine Mummery, President of ISSCR, advocated for support for early embryo research to deepen our understanding of early human development and also help with issues of infertility.

Then the ideas started coming really fast:

  • There’s a need for knowledge networks to share information in real-time not months later after results are published.
  • We need standardization across the field to make it easier to compare study results.
  • We need automation to reduce inconsistency in things like feeding and growing cells, manufacturing cells etc.
  • Equitable access to CRISPR gene-editing treatments, particularly for underserved communities and for rare diseases where big pharmaceutical companies are less likely to invest the money needed to develop a treatment.
  • Do a better job of developing combination therapies – involving stem cells and more traditional medications.

One idea that seemed to generate a lot of enthusiasm – perhaps as much due to the name that Patrik Brundin of the Van Andel Institute gave it – was the creation of a CIRM Hotel California, a place where researchers could go to learn new techniques, to share ideas, to collaborate and maybe take a nice cold drink by the pool (OK, I just made that last bit up to see if you were paying attention).

The meeting was remarkable not just for the flood of ideas, but also for its sense of collegiality.  Peter Marks, the director of the Food and Drug Administration’s Center for Biologics Evaluation and Research (FDA-CBER) captured that sense perfectly when he said the point of everyone working together, collaborating, sharing information and data, is to get these projects over the finish line. The more we work together, the more we will succeed.

Unlocking a key behind why our bones get weaker as we age

Magnified image of a bone with osteoporosis. Photo Courtesy Sciencephoto.com

Getting older brings with it a mixed bag of items. If you are lucky you can get wiser. If you are not so lucky you can get osteoporosis. But while scientists don’t know how to make you wiser, they have gained some new insights into what makes bones weak and so they might be able to help with the osteoporosis.

Around 200 million people worldwide suffer from osteoporosis, a disease that causes bones to become so brittle that in extreme cases even coughing can lead to a fracture.

Scientists have known for some time that the cells that form the building blocks of our skeletons are found in the bone marrow. They are called mesenchymal stem cells (MSCs) and they have the ability to turn into a number of different kinds of cells, including bone or fat. The keys to deciding which direction the MSCs take are things called epigenetic factors, these basically control which genes are switched on or off and in what order. Now researchers from the UCLA School of Dentistry have identified an enzyme that plays a critical role in that process.

The team found that when the enzyme KDM4B is missing in MSCs those cells are more likely to become fat cells rather than bone cells. Over time that leads to weaker bones and more fractures.

In a news release Dr. Cun-Yu Wang, the lead researcher, said: “We know that bone loss comes with age, but the mechanisms behind extreme cases such as osteoporosis have, up until recently, been very vague.”

To see if they were on the right track the team created a mouse model that lacked KDM4B. Just as they predicted the MSCs in the mouse created more fat than bone, leading to weaker skeletons.

They also looked at mice who were placed on a high fat diet – something known to increase bone loss and weaker bones in people – and found that the diet seemed to reduce KDM4B which in turn produced weaker bones.

In the news release Dr. Paul Krebsbach, Dean of the UCLA School of Dentistry, said the implications for the research are enormous. “The work of Dr. Wang, his lab members and collaborators provides new molecular insight into the changes associated with skeletal aging. These findings are an important step towards what may lead to more effective treatment for the millions of people who suffer from bone loss and osteoporosis.”

The study is published in the journal Cell Stem Cell.

Scientists use stem cells to create Neanderthal-like “mini-brain”

Alysson R. Muotri, Ph.D.

The evolution of modern day humans has always been a topic that has been shrouded in mystery. Some of what is known is that Neanderthals, an archaic human species that lived on this planet up until about 11,700 years ago, interbred with our species (Homo sapiens) at some point in time. Although their brains were about as big as ours, anthropologists think they must have worked differently due to the fact that they never achieved the sophisticated technology and artistry modern humans have.

Since brains do not fossilize, it has been challenging to see how these two early human species have changed over time. To help answer this question, Dr. Alysson Muotri and his team at UC San Diego created so-called “mini-brains” using stem cells and gene editing technology to better understand how the Neanderthal brain might have functioned.

For this study, Dr. Muotri and his team closely evaluated the differences in genes between modern day humans and Neanderthals. They found a total of 61 different genes, but for this study focused on one in particular that plays a role in influencing early brain development.

Brain organoids that carry a Neanderthal gene.
Image courtesy of the Muotri Lab and UCSD

Using gene editing technology, the team introduced the Neanderthal version of the gene into human stem cells. These stem cells, which have the ability to become various cell types, were then used to create brain cells. These cells eventually formed brain organoids or “mini-brains”, 3D models made of cells that can be used to analyze certain features of the human brain. Although they are far from perfect replicas, they can be used to study physical structure and other characteristics. In a previous CIRM funded study, Dr. Muotri had used “mini-brains” to model an autism spectrum disorder and help test treatments.

Dr. Muotri and his team found that the Neanderthal-like brain organoids looked very different than modern human brain organoids, having a distinctly different shape. Upon further analysis, the team found that modern and Neanderthal-like brain organoids also differed in the way their cells grow. Additionally, the way in which connections between neurons formed as well as the proteins involved in forming these connections differed between the two organoids. Finally, electrical impulses displayed higher activity at earlier stages, but didn’t synchronize in networks in Neanderthal-like brain organoids.

According to Muotri, the neural network changes in Neanderthal-like brain organoids mimic the way newborn primates acquire new abilities more rapidly than human newborns.

In a news release from UCSD, Dr. Muotri discusses the next steps in advancing this research.

“This study focused on only one gene that differed between modern humans and our extinct relatives. Next we want to take a look at the other 60 genes, and what happens when each, or a combination of two or more, are altered. We’re looking forward to this new combination of stem cell biology, neuroscience and paleogenomics.”

The full results of this study were published in Science.

Biotechnology companies join forces in developing treatment for X-SCID

Jasper Therapeutics, Inc., a biotechnology company focused on blood stem cell therapies, and Graphite Bio, Inc., a biotechnology company focused on gene editing therapies to treat or cure serious diseases, announced a research and clinical collaboration for a treatment for X-SCID.

X-SCID, which stands for X-linked severe combined immunodeficiency, is a genetic disorder that interferes with the normal development of the immune system, leaving infants vulnerable to infections that most people can easily fight off. One treatment for X-SCID involves a blood stem cell transplant, in which the patient’s defective stem cells are wiped out with chemotherapy or radiation to make room for normal blood stem cells to take their place. Unfortunately, the problem with chemotherapy or radiation in young infants is that it can lead to lifelong effects such as neurological impairment, growth delays, infertility, and risk of cancer.

Fortunately, Jasper Therapeutics has developed JSP191, a non-toxic alternative to chemotherapy and radiation. It is an antibody that works by targeting and removing the defective blood forming stem cells. The approach has previously been used in a CIRM-funded clinical trial ($20M award) for X-SCID.

Graphite Bio has developed GPH201, the first-in-human investigational blood stem cell treatment that will be evaluated as a potential cure for patients suffering from X-SCID. GPH201 is generated using precise and efficient gene editing technology, It works by directly replacing a defective gene that causes problems with the immune system. The hope is that GPH201 will ultimately lead to the production of fully functional, healthy immune cells.

The ultimate goal of this collaboration is to use JSP191 as the non-toxic alternative to chemotherapy in patients in order to remove their defective blood stem cells. After that, the gene editing blood stem cell technology developed by Graphite Bio can be introduced to patients in order to treat X-SCID. The two companies have agreed to collaborate on research, and potentially a clinical study, evaluating JSP191 as the non-toxic conditioning agent for GPH201.

In a press release, Josh Lehrer, M.Phil., M.D., chief executive officer at Graphite Bio, expressed excitement about the collaboration between the two companies.

“This collaboration with Jasper demonstrates our shared commitment to pioneering novel therapeutic approaches with the potential to significantly improve the treatment experiences of individuals with devastating conditions who stand to benefit from gene replacement therapies, initially for patients with XSCID. GPH201 harnesses our targeted gene integration platform to precisely target the defective gene that causes XSCID and replace it with a normal copy.”

In the same press release, Bill Lis, executive chairman and CEO of Jasper Therapeutics, also expressed optimism in regards to the two companies teaming up.

“Our collaboration with Graphite Bio is an exciting opportunity to further advance the field of curative gene correction by combining a targeted gene integration platform with our first-in-class targeted CD117 antibody, JSP191, that has already demonstrated preliminary clinical efficacy and safety as a conditioning agent in X-SCID patients and those with blood cancers undergoing allogeneic hematopoietic stem cell transplant.”

Graphite Bio is also developing gene editing technology to help treat sickle cell disease.  It is currently supported by a CIRM  late stage preclinical grant ($4.8M award). Th goal is to complete the final preclinical studies, which will allow Graphite Bio to start clinical studies of the sickle cell disease gene therapy in sickle cell patients in 2021.

De-stressing stem cells and the Bonnie & Clyde of stem cells

Dr. John Cashman

The cells in our body are constantly signalling with each other, it’s a critical process by which cells communicate not just with other cells but also with elements within themselves. One of the most important signalling pathways is called Wnt. This plays a key role in early embryonic and later development. But when Wnt signalling goes wrong, it can also help spur the growth of cancer.

Researchers at the Human BioMolecular Research Institute (HBRI) and Stanford University, have reported on a compound that can trigger a cascade of events that create stress and ultimately impact Wnt’s ability to control the ability of cells to repair themselves.

In a news release Dr. Mark Mercola, a co-author of a CIRM-funded study – published in the journal Cell Chemical Biology – says this is important: “because it explains why stressed cells cannot regenerate and heal tissue damage. By blocking the ability to respond to Wnt signaling, cellular stress prevents cells from migrating, replicating and differentiating.”

The researchers discovered a compound PAWI-2 that shows promise in blocking the compound that causes this cascade of problems. Co-author Dr. John Cashman says PAWI-2 could lead to treatments in a wide variety of cancers such as pancreatic, breast, prostate and colon cancer.

“As anti-cancer PAWI-2 drug development progresses, we expect PAWI-2 to be less toxic than current therapeutics for pancreatic cancer, and patients will benefit from improved safety, less side effects and possibly with significant cost-savings.”

Dr. Catriona Jamieson: Photo courtesy Moores Cancer Center, UCSD

Speaking of cancer….

Stem cells have many admirable qualities. However, one of their less admirable ones is their ability to occasionally turn into cancer stem cells. Like regular stem cells these have the ability to renew and replicate themselves over time, but as cancer stem cells they use that ability to help fuel the growth and spread of cancer in the body. Now, researchers at U.C. San Diego are trying to better understand how those regular stem cells become cancer stem cells, so they can stop that process.

In a CIRM-funded study Dr. Catriona Jamieson and her team identified two molecules, APOBEC3C and ADAR1, that play a key role in this process.

In a news release Jamieson said: “APOBEC3C and ADAR1 are like the Bonnie and Clyde of pre-cancer stem cells — they drive the cells into malignancy.”

So they studied blood samples from 54 patients with leukemia and 24 without. They found that in response to inflammation, APOBEC3C promotes the rapid production of pre-leukemia stem cells. That in turn enables ADAR1 to go to work, interfering with gene expression in a way that helps those pre-leukemia stem cells turn into leukemia stem cells.

They also found when they blocked the action of ADAR1 or silenced the gene in patient cells in the laboratory, they were able to stop the formation of leukemia stem cells.

The study is published in the journal Cell Reports.

Surviving with Joy

Dr. Tippi MacKenzie (left) of UCSF Benioff Children’s Hospital San Francisco, visits with newborn Elianna and parents Nichelle Obar and Chris Constantino. Photo by Noah Berger

Alpha thalassemia major is, by any stretch of the imagination, a dreadful, heart breaker of a disease. It’s caused by four missing or mutated genes and it almost always leads to a fetus dying before delivery or shortly after birth. Treatments are limited and in the past many parents were told that all they can do is prepare for the worst.

Now, however, there is new hope with new approaches, including one supported by CIRM, helping keep these children alive and giving them a chance at a normal life.

Thalassemias are a group of blood disorders that affect the way the body makes hemoglobin, which helps in carrying oxygen throughout the body. In alpha thalassemia major it’s the lack of alpha globin, a key part of hemoglobin, that causes the problem. Current treatment requires in blood transfusions to the fetus while it is still in the womb, and monthly blood transfusions for life after delivery, or a bone marrow transplant if a suitable donor is identified.

A clinical trial run by University of California San Francisco’s Dr. Tippi MacKenzie – funded by CIRM – is using a slightly different approach. The team takes stem cells from the mother’s bone marrow and then infuses them into the fetus. If accepted by the baby’s bone marrow, these stem cells can then mature into healthy blood cells. The hope is that one day this method will enable children to be born with a healthy blood supply and not need regular transfusions.

Treating these babies, saving their lives, is the focus of a short film from UCSF called “Surviving with Joy”. It’s a testament to the power of medicine, and the courage and resilience of parents who never stopped looking for a way to help their child.

Tissues are optional but advised.

CIRM funded researchers discover link between Alzheimer’s gene and COVID-19

Dr. Yanhong Shi (left) and Dr. Vaithilingaraja Arumugaswami (right)

All this month we are using our blog and social media to highlight a new chapter in CIRM’s life, thanks to the voters approving Proposition 14. We are looking back at what we have done since we were created in 2004, and also looking forward to the future. Today we focus on groundbreaking CIRM funded research related to COVID-19 that was recently published.

It’s been almost a year since the world started hearing about SARS-CoV-2, the virus that causes COVID-19.  In our minds, the pandemic has felt like an eternity, but scientists are still discovering new things about how the virus works and if genetics might play a role in the severity of the virus.  One population study found that people who have ApoE4, a gene type that has been found to increase the risk of developing Alzheimer’s, had higher rates of severe COVID-19 and hospitalizations.

It is this interesting observation that led to important findings of a study funded by two CIRM awards ($7.4M grant and $250K grant) and conducted by Dr. Yanhong Shi at City of Hope and co-led by Dr. Vaithilingaraja Arumugaswami, a member of the UCLA Broad Stem Cell Research Center.  The team found that the same gene that increases the risk for Alzheimer’s disease can increase the susceptibility and severity of COVID-19.

At the beginning of the study, the team was interested in the connection between SARS-CoV-2 and its effect on the brain.  Due to the fact that patients typically lose their sense of taste and smell, the team theorized that there was an underlying neurological effect of the virus.  

The team first created neurons and astrocytes.  Neurons are cells that function as the basic working unit of the brain and astrocytes provide support to them.  The neurons and astrocytes were generated from induced pluripotent stem cells (iPSCs), which are a kind of stem cell that can become virtually any type of cell and can be created by “reprogramming” the skin cells of patients.  The newly created neurons and astrocytes were then infected with SARS-CoV-2 and it was found that they were susceptible to infection.

Next, the team used iPSCs to create brain organoids, which are 3D models that mimic certain features of the human brain.  They were able to create two different organoid models: one that contained astrocytes and one without them.  They infected both brain organoid types with the virus and discovered that those with astrocytes boosted SARS-CoV-2 infection in the brain model. 

The team then decided to further study the effects of ApoE4 on susceptibility to SARS-CoV-2.  They did this by generating neurons from iPSCs “reprogrammed” from the cells of an Alzheimer’s patient.  Because the iPSCs were derived from an Alzheimer’s patient, they contained ApoE4.  Using gene editing, the team modified some of the ApoE4 iPSCs created so that they contained ApoE3, which is a gene type considered neutral.  The ApoE3 and ApoE4 iPSCs were then used to generate neurons and astrocytes.

The results were astounding.  The ApoE4 neurons and astrocytes both showed a higher susceptibility to SARS-CoV-2 infection in comparison to the ApoE3 neurons and astrocytes.  Moreover, while the virus caused damage to both ApoE3 and ApoE4 neurons, it appeared to have a slightly more severe effect on ApoE4 neurons and a much more severe effect on ApoE4 astrocytes compared to ApoE3 neurons and astrocytes. 

“Our study provides a causal link between the Alzheimer’s disease risk factor ApoE4 and COVID-19 and explains why some (e.g. ApoE4 carriers) but not all COVID-19 patients exhibit neurological manifestations” says Dr. Shi. “Understanding how risk factors for neurodegenerative diseases impact COVID-19 susceptibility and severity will help us to better cope with COVID-19 and its potential long-term effects in different patient populations.”

In the last part of the study, the researchers tested to see if the antiviral drug remdesivir inhibits virus infection in neurons and astrocytes.  They discovered that the drug was able to successfully reduce the viral level in astrocytes and prevent cell death.  For neurons, it was able to rescue them from steadily losing their function and even dying. 

The team says that the next steps to build on their findings is to continue studying the effects of the virus and better understand the role of ApoE4 in the brains of people who have COVID-19.  Many people that developed COVID-19 have recovered, but long-term neurological effects such as severe headaches are still being seen months after. 

“COVID-19 is a complex disease, and we are beginning to understand the risk factors involved in the manifestation of the severe form of the disease” says Dr. Arumugaswami.  “Our cell-based study provides possible explanation to why individuals with Alzheimer’s’ disease are at increased risk of developing COVID-19.”

The full results to this study were published in Cell Stem Cell.

Progress in the fight against Sickle Cell Disease

Marissa Cors, sickle cell disease patient advocate

Last November Marissa Cors, a patient advocate in the fight against Sickle Cell Disease (SCD), told the Stem Cellar “A stem cell cure will end generations of guilt, suffering, pain and early death. It will give SCD families relief from the financial, emotional and spiritual burden of caring someone living with SCD. It will give all of us an opportunity to have a normal life. Go to school, go to work, live with confidence.” With each passing month it seems we are getting closer to that day.

CIRM is funding four clinical trials targeting SCD and another project we are supporting has just been given the green light by the Food and Drug Administration to start a clinical trial. Clearly progress is being made.

Yesterday we got a chance to see that progress. We held a Zoom event featuring Marissa Cors and other key figures in the fight against SCD, CIRM Science Officer Dr. Ingrid Caras and Evie Junior. Evie is a pioneer in this struggle, having lived with sickle cell all his life but now hoping to live his life free of the disease. He is five months past a treatment that holds out the hope of eradicating the distorted blood cells that cause such devastation to people with the disease.

You can listen to his story, and hear about the other progress being made. Here’s a recording of the Zoom event.

You can also join Marissa every week on her live event on Facebook, Sickle Cell Experience Live.

Inspiring new documentary about stem cell research

Poster for the documentary “Ending Disease”

2020 has been, to say the very least, a difficult and challenging year for all of us. But while the focus of the world has, understandably, been on the coronavirus there was also some really promising advances in stem cell research. Those advances are captured in a great new documentary called Ending Disease.

The documentary is by Emmy award-winning filmmaker Joe Gantz. In it he follows ten people who are facing life-threatening or life-changing diseases and injuries and who turn to pioneering stem cell therapies for help.

It’s an inspiring documentary, one that reminds you of the real need for new treatments and the tremendous hope and promise of stem cell therapies. Here’s a look at a trailer for Ending Disease.

You can see an exclusive screening of Ending Disease on Friday, January 8th, 2021 at 5:00pm PST.

After the livestream, there will be a live Q&A session where former members of the successful Proposition 14 campaign team – which refunded CIRM with an additional $5.5 billion – will be joined by CIRM’s President and CEO Dr. Maria Millan, talking about what lies ahead for CIRM and the future of stem cell research.

To purchase a ticket, click here. It only costs $12 and 50% of the ticket sales proceeds will go to Americans for Cures to help them continue to advocate for the advancement of stem cell research, and more importantly, for the patients and families to whom stem cell research provides so much hope.

If you need any extra persuading that it’s something you should definitely put on our calendar, here’s a letter from the film maker Joe Gantz.

I am the director of the documentary Ending Disease: The Stem Cell, Anti-Cancer T-Cell, & Antibody Revolution In Medicine, a film that will help inform people about the progress that’s been made in this field and how people with their lives on the line are now able to benefit from these new regenerative therapies. 

I was granted unprecedented access to ten of the first generation of clinical trials using stem cell and regenerative medicine to treat and cure many of the most devastating diseases and conditions including: brain cancer, breast cancer, leukemia and lymphoma, HIV, repairing a broken spinal cord, retinitis pigmentosa and SCID. The results are truly inspiring.

This is personal for me.  After spending four years making this documentary, I was diagnosed with bladder cancer. Upon diagnosis, I immediately felt the same desperation as millions of families who are in search of a medical breakthrough. I understood, on a personal level, what the patients we followed in the film all knew: when you are diagnosed with a disease, there is a narrow window of time in which you can effectively seek a life-saving treatment or cure. If treatment becomes available outside of that window, then it is too late. However, Ending Disease shows that with continued support for regenerative medicine, we can create a near future in which one-time cures and highly mitigating therapies are available to patients for a whole host of diseases.

Best regards,

Joe