Cancers of the blood, bone marrow and lymph nodes (also called hematologic malignancies) are the most common form of cancer in children and young adults. Current treatments can be effective but can also pose life-threatening health risks to the child. Now researchers at Stanford have developed a new approach and the Board of the California Institute for Regenerative Medicine (CIRM) voted to support that approach in a clinical trial.
The Board approved investing $11,996,634 in the study, which is the Stem Cell Agency’s 76th clinical trial.
The current standard of care for cancers such as acute leukemias and lymphomas is chemotherapy and a bone marrow (also called HSCT) transplant. However, without a perfectly matched donor the risk of the patient’s body rejecting the transplant is higher. Patients may also be at greater risk of graft vs host disease (GVHD), where the donor cells attack the patient’s body. In severe cases GVHD can be life-threatening.
Dr. Maria Grazia Roncarolo and her team at Stanford will test an immunotherapy cell approach using a therapy that is enriched with specialized immune cells called type 1 regulatory T (Tr1) cells. These cells will be infused into the patient following the bone marrow transplant. Both the Tr1 cells and the bone marrow will come from the same donor. The hope is this will help provide the patient’s immune system with these regulatory cells to combat life-threatening graft versus host disease and increase the success of treatment and bone marrow (HSCT) transplant.
“Every year around 500 children receive stem cell transplants in California, and while many children do well, too many experiences a rejection of the transplant or a relapse of the cancer,” says Dr. Maria T. Millan, President and CEO of CIRM. “Finding an improved therapy for these children means a shorter stay in the hospital, less risk of the need for a second transplant, and a greater quality of life for the child and the whole family.”
The CIRM Board has previously approved funding for 12 other clinical trials targeting cancers of the blood. You can read about them here.
People say that with age comes wisdom, kindness and confidence. What they usually don’t say is that it also comes with aches and pains and problems we didn’t have when we were younger. For example, as we get older our bones get thinner and more likely to break and less likely to heal properly.
That’s a depressing opening paragraph isn’t it. But don’t worry, things get better from here because new research from Germany has found clues as to what causes our bones to become more brittle, and what we can do to try and stop that.
Researchers at the Max Planck Institute for Biology of Ageing and CECAD Cluster of Excellence for Ageing Research at the University of Cologne have identified changes in stem cells from our bone marrow that seem to play a key role in bones getting weaker as we age.
To explain this we’re going to have to go into the science a little, so bear with me. One of the issues the researchers focused on is the role of epigenetics, this is genetic information that doesn’t change the genes themselves but does change their activity. Think of it like a light switch. The switch doesn’t change the bulb, but it does control when it’s on and when it’s off. So this team looked at the epigenome of MSCs, the stem cells found in the bone marrow. These cells play a key role in the creation of cartilage, bone and fat cells.
In a news release, Dr. Andromachi Pouikli, one of the lead researchers in the study, says these MSCs don’t function as well as we get older.
“We wanted to know why these stem cells produce less material for the development and maintenance of bones as we age, causing more and more fat to accumulate in the bone marrow. To do this, we compared the epigenome of stem cells from young and old mice. We could see that the epigenome changes significantly with age. Genes that are important for bone production are particularly affected.”
So, they took some stem cells from the bone marrow of mice and tested them with a solution of sodium acetate. Now sodium acetate has a lot of uses, including being used in heating pads, hand warmers and as a food seasoning, but in this case the solution was able to make it easier for enzymes to get access to genes and boost their activity.
“This treatment impressively caused the epigenome to rejuvenate, improving stem cell activity and leading to higher production of bone cells,” Pouikli said.
So far so good. But does this work the same way in people? Maybe so. The team analyzed MSCs from people who had undergone hip surgery and found that they showed the same kind of age-related changes as the cells from mice.
Clearly there’s a lot more work to do before we can even think about using this finding as a solution to aging bones. But it’s an encouraging start.
Alzheimer’s research has been in the news a lot lately, and not for the right reasons. The controversial decision by the Food and Drug Administration (FDA) to approve the drug Aduhelm left many people wondering how, when, or even if it should be used on people battling Alzheimer’s disease. Now a new study is raising questions about many of the clinical trials used to test medications like Aduhelm.
The research, published in the journal Jama Neurology, looked at 302 studies on dementia published in 2018 and 2019. Most of these studies were carried out in North America or Europe, and almost 90 percent of those studied were white.
In an accompanying editorial in the journal, Dr. Cerise Elliott, PhD, of the National Institute on Aging (NIA) in Bethesda, Maryland, and co-authors wrote that this limited the value of the studies: “This, combined with the fact that only 22% of the studies they analyzed even reported on race and ethnicity, and of those, a median 89% of participants were white, reflects the fact that recruitment for research participation is challenging; however, it is unacceptable that studies continue to fail to report participant demographics and that publishers allow such omissions.”
That bias is made all the more glaring by the fact that recent data from the Centers for Disease Control and Prevention shows that among people 65 and older, the Black community has the highest prevalence of Alzheimer’s disease and related dementias (13.8%), followed by Latinx (12.2%), non-Hispanic white (10.3%), American Indian and Alaskan Native (9.1%), and Asian and Pacific Islander (8.4%) populations.
The researchers admitted that the limited sample size – more than 40 percent of the studies they looked at included fewer than 50 patients – could have impacted their findings. Even so this clearly suggests there is a huge divide between the people at greatest risk of developing Alzheimer’s, or some other form of dementia, and the people being studied.
In the editorial, Elliott and his colleagues wrote that without a more diverse and balanced patient population this kind of research: “will continue to underrepresent people most affected by the disease and perpetuate systems that exclude important valuable knowledge about the disease.”
“For years, the Journal has published studies that simply do not include enough participants from the racial and ethnic groups that are disproportionately affected by the illnesses being studied to support any conclusions about their treatment. In the United States, for example, Black Americans have high rates of hypertension and chronic kidney disease, Hispanic Americans have the highest prevalence of nonalcoholic fatty liver disease, Native Americans are disproportionately likely to have metabolic syndrome, and Asian Americans are at particular risk for hepatitis B infection and subsequent cirrhosis, but these groups are frequently underrepresented in clinical trials and cohort studies.”
“For too long, we have tolerated conditions that actively exclude groups from critical resources in health care delivery, research, and education. This exclusion has tragic consequences and undermines confidence in the institutions and the people who are conducting biomedical research. And clinicians cannot know how to optimally prevent and treat disease in members of communities that have not been studied.”
The encouraging news is that, finally, people are recognizing the problem and trying to come up with ways to correct it. The not so encouraging is that it took a pandemic to get us to pay attention.
At CIRM we are committed to being part of the solution. We are now requiring everyone who applies to us for funding to have a written plan on Diversity, Equity and Inclusion, laying out how their work will reflect the diversity of California. We know this will be challenging for all of us. But the alternative, doing nothing, is no longer acceptable.
As far as Aldo Pourchet is concerned you are never too young to learn about stem cells. Aldo should know. He’s a molecular and cellular biologist and the co-founder and CEO of Omios Bio, which develops immunotherapies for cancer, infectious and inflammatory diseases.
And now Aldo is the author of a children’s book about stem cells. The book is “Nano’s Journey! A Little Stem Cell Visits the Heart and Lungs.” It’s the story of Nano, a stem cell who doesn’t know what kind of cell she wants to be when she grows up, so she goes on a journey through the body, exploring all the different kinds of cell she could be.
It’s a really sweet book, beautifully illustrated, and written in a charming way to engage children between the ages of 5 and 8. I asked Aldo what made him want to write a book like this.
“I was interested in providing very general knowledge such as the principleof life, the basic logics of nature and at the same time to entertain. It wasvery important for it not to be a textbook.
“Why Stem cells? Because it is the most fascinating biology and they are at the origin of an organism and throughout its life play an essential role. They evolve and transform, so they have a story that unfolds. An analogy with children maybe. It’s easy to imagine children are like stem cells, trying to decide who they are, while adults are like differentiated cells because they have already decided.
“For the kids to appropriate the story, I thought that humanizing cells was important. I wanted children to identify themselves with the cells andespecially Nano, the little girl main character. It’s a book written for the children, in the first place. We tell the story at their level. Not try to bring them up to the level of life science.
Aldo says right from the start he had a clear idea of who he wanted the lead character to be.
“I think the world needs more female leaders, more female voices andinfluence in general and in every domain. So quite early it became naturalfor me that Nano would be a girl and also would have a strong character,curious and adventurous.
“Blasto came later because I was looking for a companion to share the adventure with Nano. Blasto is a fibroblast so he is not supposed to leave the Bone Marrow but fibroblasts are everywhere in our organism so I thought it was an acceptable stretch.
The drawings in the book are delightful, colorful and fun. Aldo says he had some ideas, rounded shapes for the cells for example and a simple design that reflected the fact that there are no lines in nature. Illustrator Jen Yoon took it from there:
“Based on Aldo’s direction and imagination, I envisioned the style like drawings on a chalkboard. Soft curves with rough textures. After that everything went smoothly. Following Nano’s journey with my iPad pencil, it felt like a boat ride at an amusement park.”
The books are written to be read aloud by parents, adults and teachers to kids. But, spoiler alert, we don’t find out what cell Nano decides to be in this book. She’s going to have more adventures in other books before she makes up her mind.
When we think of lung cancer we typically tend to think it’s the end result of years of smoking cigarettes. But, according to the Centers for Disease Control and Prevention, between 10 and 20 percent of cases of lung cancer (20,000 to 40,000 cases a year) happen to non-smokers, people who have either never smoked or smoked fewer than 100 cigarettes in their life. Now researchers have found that there are different genetic types of cancer for smokers and non-smokers, and that might mean the need for different kinds of treatment.
A team at the National Cancer Institute did whole genome sequencing on tumors from 232 never-smokers who had lung cancer. In an interview with STATnews, researcher Maria Teresa Landi said they called their research the Sherlock-Lung study, after the famous fictional pipe-smoking detective Sherlock Holmes. “We used a detective approach. By looking at the genome of the tumor, we use the changes in the tumors as a footprint to follow to infer the causes of the disease.”
They also got quite creative in naming the three different genetic subtypes they found. Instead of giving them the usual dry scientific names, they called them piano, mezzo-forte and forte; musical terms for soft, medium and loud.
Half of the tumors in the non-smokers were in the piano group. These were slow growing with few mutations. The median latency period for these (the time between being exposed to something and being diagnosed) was nine years. The mezzo-forte group made up about one third of the cases. Their cancers were more aggressive with a latency of around 14 weeks. The forte group were the most aggressive, and the ones that most closely resembled smokers’ cancer, with a latency period of just one month.
So, what is the role of stem cells in this research? Well, in the study, published in the journal Nature Genetics the team found that the piano subtype seemed to be connected to genes that help regulate stem cells. That complicates things because it means that the standard treatments for lung cancer that work for the mezzo-forte and forte varieties, won’t work for the piano subtype.
“If this is true, it changes a lot of things in the way we should think of tumorigenesis,” Dr. Landi said.
With that in mind, and because early-detection can often be crucial in treating cancer, what can non-smokers do to find out if they are at risk of developing lung cancer? Well, right now there are no easy answers. For example, the U.S. Preventive Services Task Force does not recommend screening for people who have never smoked because regular CT scans could actually increase an otherwise healthy individual’s risk of developing cancer.
For Sharif Tabebordbar, finding a gene therapy for genetic muscle wasting diseases was personal. When he was a teenager, his father was diagnosed with a rare genetic muscle disease that eventually left him unable to walk.
In an interview with the Broad Institute at MIT he said: “I watched my dad get worse and worse each day. It was a huge challenge to do things together as a family – genetic disease is a burden on not only patients but families. I thought: This is very unfair to patients and there’s got to be a way to fix this. That’s been my motivation during the 10 years that I’ve been working in the field of gene therapy.”
That commitment now seems to be paying off. In a study published in the journal Cell, Tabebordar and his team at MIT and Harvard showed how they have developed a new, safer and easier way to deliver genes to help repair wasting muscles.
In earlier treatments targeting genetic muscle diseases, researchers used a virus to help deliver the gene that would correct the problem. However, to be effective they had to use high doses of the gene-carrying virus to ensure it reached as many muscles throughout the body as possible. But this meant that more of the payload often ended up in the liver and that led to severe side effects in some patients, even a few deaths.
The usual delivery method of these gene-correcting therapies is something called an adeno-associated virus (AAV), so Dr. Tabebordar set out to develop a new kind of AAV, one that would be safer for patients and more effective at tackling the muscle wasting.
They started by taking an adeno-associated virus called AAV9 and then set out about tweaking its capsid – that’s the outer shell that helps protect the virus and allows it to attach to another cell and penetrate it to deliver the corrected gene. They called this new viral vector MyoAAV and in tests it quickly showed it had an enhanced ability to deliver genes into cells.
The team showed that it not only was around 10 times more efficient at reaching muscle than other AAVs, but that it also reduces the amount that reaches the liver. This meant that MyoAAV could achieve impressive results in doses up to 250 times lower than those previously used.
“All of these results demonstrate the broad applicability of the MyoAAV vectors for delivery to muscle. These vectors work in different disease models and across different ages, strains and species, which demonstrates the robustness of this family of AAVs. We have an enormous amount of information about this class of vectors from which the field can launch many exciting new studies.”
Having the right tools to do a job is important. Try using a large screwdriver to tighten the screws on your glasses and you quickly appreciate that it’s not just the type of tool that’s important, it’s also the size. The same theory applies to gene editing. And now researchers at Stanford have developed a tool that can take on even the tiniest of jobs.
The tool involves the use of CRISPR. You may well have heard about CRISPR. The magazine New Scientist described it this way: “CRISPR is a technology that can be used to edit genes and, as such, will likely change the world.” For example, CIRM is funding research using CRISPR to help children born with severe combined immunodeficiency, a rare, fatal immune disorder.
There’s just one problem. Right now, CRISPR is usually twinned with a protein called Cas9. Together they are used to remove unwanted genes and insert a corrected copy of the bad gene. However, that CRISPR-Cas9 combination is often too big to fit into all our cells. That may seem hard to understand for folks like me with a limited science background, but trust the scientists, they aren’t making this stuff up.
To address that problem, Dr. Stanley Qi and his team at Stanford created an even smaller version, one they call CasMINI, to enable them to go where Cas9 can’t go. In an article on Fierce Biotech, Dr. Qi said this mini version has some big benefits: “If people sometimes think of Cas9 as molecular scissors, here we created a Swiss knife containing multiple functions. It is not a big one, but a miniature one that is highly portable for easy use.”
How much smaller is the miniature version compared to the standard Cas9? About half the size, 529 amino acids, compared to Cas9’s 1,368 amino acids.”
The team conclude their study in the journal Molecular Cellsaying this could have widespread implications for the field: “This provides a new method to engineer compact and efficient CRISPR-Cas effectors that can be useful for broad genome engineering applications, including gene regulation, gene editing, base editing, epigenome editing, and chromatin imaging.”
Adrienne Shapiro and Marissa Cors are a remarkable pair by any definition. The mother and daughter duo share a common bond, and a common goal. And they are determined not to let anyone stop them achieving that goal.
Marissa was born with sickle cell disease (SCD) a life-threatening genetic condition where normally round, smooth red blood cells are instead shaped like sickles. These sickle cells are brittle and can clog up veins and arteries, blocking blood flow, damaging organs, and increasing the risk of strokes. It’s a condition that affects approximately 100,000 Americans, most of them Black.
Adrienne became a patient advocate, founding Axis Advocacy, after watching Marissa get poor treatment in hospital Emergency Rooms. Marissa often talks about the way she is treated like a drug-seeker simply because she knows what medications she needs to help control excruciating pain on her Sickle Cell Experience Live events on Facebook.
Now the two are determined to ensure that no one else has to endure that kind of treatment. They are both fierce patient advocates, vocal both online and in public. And we recently got a chance to sit down with them for our podcast, Talking ‘Bout (re) Generation. These ladies don’t pull any punches.
As someone who is not always as diligent as he would like to be about sending birthday cards on time, I’m used to sending belated greetings to people. So, I have no shame in sending belated greetings to four CIRM grantees who were inducted into the National Academy of Medicine in 2020.
I say four, but it’s really three and a half. I’ll explain that later.
Being elected to the National Academy of Medicine is, in the NAM’s own modest opinion, “considered one of the highest honors in the fields of health and medicine and recognizes individuals who have demonstrated outstanding professional achievement and commitment to service.”
To be fair, NAM is right. The people elected are among the best and brightest in their field and membership is by election from the other members of NAM, so they are not going to allow any old schmuck into the Academy (which could explain why I am still waiting for my membership).
The CIRM grantees elected last year are:
Antoni Ribas, MD, PhD, professor of medicine, surgery, and molecular and medical pharmacology, U. C. Los Angeles.
Dr. Ribas is a pioneer in cancer immunology and has devoted his career to developing new treatments for malignant melanoma. When Dr. Ribas first started malignant melanoma was an almost always fatal skin cancer. Today it is one that can be cured.
In a news release Dr. Ribas said it was a privilege to be honored by the Academy: “It speaks to the impact immunotherapy has played in cancer research. When I started treating cases of melanoma that had metastasized to other organs, maybe 1 in 20 responded to treatment. Nobody in their right mind wanted to be a specialist in this field. It was the worst of the worst cancers.”
Dr. Goldberg was honored for his contribution to the understanding of vision loss and ways to reverse it. His lab has developed artificial retinas that transmit images down the optic nerve to the brain through tiny silicon chips implanted in the eye. He has also helped use imaging technology to better improve our ability to detect damage in photoreceptor cells (these are cells in the retina that are responsible for converting light into signals that are sent to the brain and that give us our color vision and night vision)
In a news release he expressed his gratitude saying: “I look forward to serving the goals of the National Academies, and to continuing my collaborative research efforts with my colleagues at the Byers Eye Institute at Stanford and around the world as we further our efforts to combat needless blindness.”
Dr. Anderson was honored for being a leader in the study of autoimmune diseases such as type 1 diabetes. This focus extends into the lab, where his research examines the genetic control of autoimmune diseases to better understand the mechanisms by which immune tolerance is broken.
Understanding what is happening with the immune system, figuring out why it essentially turns on the body, could one day lead to treatments that can stop that, or even reverse it by boosting immune activity.
Remember at the beginning I said that three and a half CIRM grantees were elected to the Academy, well, Canadian researcher, Dr. John Dick is the half. Why? Well, because the award we funded actually went to UC San Diego’s Dennis Carson but it was part of a Collaborative Funding Partnership Program with Dr. Dick at the University of Toronto. So, we are going to claim him as one of our own.
And he’s a pretty impressive individual to partner with. Dr. Dick is best known for developing a test that led to the discovery of leukemia stem cells. These are cells that can evade surgery, chemotherapy and radiation and which can lead to patients relapsing after treatment. His work helped shape our understanding of cancer and revealed a new strategy for curing it.
Type 1 diabetes (t1d) affects every aspect of a person’s life, from what they eat and when they eat, to when they exercise and how they feel physically and emotionally. Because the peak age for being diagnosed with t1d is around 13 or 14 years of age it often hits at a time when a child is already trying to cope with big physical and emotional changes. Add in t1d and you have a difficult time made a lot more challenging.
There are ways to control the disease. Regular blood sugar monitoring and insulin injections can help people manage their condition but those come with their own challenges. Now researchers are taking a variety of different approaches to developing new, innovative ways of helping people with t1d.
One of those companies is Encellin. They are developing a pouch-like device that can be loaded with stem cells and then implanted in the body. The pouch acts like a mini factory, releasing therapies when they are needed.
This work began at UC San Francisco in the lab of Dr. Tejal Desai – with help from CIRM funding – that led to the creation of Encellin. We recently sat down – virtually of course – with Dr. Grace Wei, the co-founder of the company to chat about their work, and their hopes for the future.
She said the decision to target t1d was an easy one:
“Type 1 diabetes is an area of great need. It’s very difficult to manage at any age but particularly in children. It affects what they can eat, what they can do, it’s a big burden on the family and can become challenging to manage when people get older.
“It’s an autoimmune disease so everyone’s disease progression is a bit different. People think it’s just a matter of you having too much blood sugar and not enough insulin, but the problem with medicines like insulin is that they are not dynamic, they don’t respond to the needs of your body as they occur. That means people can over-regulate and give themselves too much insulin for what their body needs and if it happens at night, it can be deadly.
Dr. Wei says stem cell research opens up the possibility of developing dynamic therapies, living medicines that are delivered to you by cells that respond to your dynamic needs. That’s where their pouch, called a cell encapsulation device (CED) comes in.
The pouch is tiny, only about the size of a quarter, and it can be placed just under the skin. Encellin is filling the pouch with glucose-sensitive, insulin producing islet cells, the kind of cells destroyed by t1d. The idea is that the cells can monitor blood flow and, when blood sugar is low, secrete insulin to restore it to a healthy level.
Another advantage of the pouch is that it may eliminate the need for the patient to take immunosuppressive medications.
“The pouch is really a means to protect both the patient receiving the cells and the cells themselves. Your body tends to not like foreign objects shoved into it and the pouch in one respect protects the cells you are trying to put into the person. But you also want to be able to protect the person, and that means knowing where the cells are and having a means to remove them if you need to. That’s why it’s good to have a pouch that you can put in the body, take it out if you need, and replace if needed.”
Dr. Wei says it’s a little like making tea with a tea bag. When the need arises the pouch can secrete insulin but it does so in a carefully controlled manner.
“These are living cells and they are responsive, it’s not medicine where you can overdose, these cells are by nature self-regulating.”
They have already tested their approach with a variety of different kinds of islets, in a variety of different kinds of model.
“We’ve tested for insulin production, glucose stimulation and insulin response. We have tested them in a number of animal models and those studies are supporting our submission for a first-in-human safety clinical trial.”
Dr. Wei says if this approach works it could be used for other metabolic conditions such as parathyroid disorders. And she says a lot of this might not be possible without the early funding and support from CIRM.
“CIRM had the foresight to invest in groups that are looking ahead and said it would be great to have renewable cells to transplant into the body (that function properly. We are grateful that groundwork that has been laid and are looking forward to advancing this work.”
And we are looking forward to working with them to help advance that work too.