As someone with a family history of type 1 diabetes (T1D) I know how devastating the condition can be. I also know how challenging it can be to keep it under control and the consequences of failing to do that. Not maintaining healthy blood sugar levels can have a serious impact on the heart, kidney, eyes, nerves, and blood vessels. It can even be fatal.
Right now, controlling T1D means being careful about what you eat, when you eat and how much you eat. It also means regularly checking your blood throughout the day to see if the glucose level is too high or too low. If it’s too high you need to inject insulin; if it’s too low you need to take a fast-acting carbohydrate such as fruit juice or glucose to try and restore it to a healthy level.
That’s why two new approaches to T1D that CIRM has supported are so exciting. They both use small devices implanted under the skin that contain stem cells. The cells can both monitor blood sugar and, if it’s too high, secrete insulin to bring it down.
We sat down with two key members of the Encellin and ViaCyte teams, Dr. Crystal Nyitray and Dr. Manasi Jaiman, to talk about their research, how it works, and what it could mean for people with T1D. That’s in the latest episode of our podcast ‘Talking ‘Bout (re)Generation’.
It’s always lovely to end the week on a bright note and that’s certainly the case this week, thanks to some encouraging news about CIRM-funded research targeting blood disorders that affect the immune system.
Stanford’s Dr. Rosa Bacchetta and her team learned that their proposed therapy for IPEX Syndrome had been given the go-ahead by the Food and Drug Administration (FDA) to test it in people in a Phase 1 clinical trial.
IPEX Syndrome (it’s more formal and tongue twisting name is Immune dysregulation Polyendocrinopathy Enteropathy X-linked syndrome) is a life-threatening disorder that affects children. It’s caused by a mutation in the FOXP3 gene. Immune cells called regulatory T Cells normally function to protect tissues from damage but in patients with IPEX syndrome, lack of functional Tregs render the body’s own tissues and organs to autoimmune attack that could be fatal in early childhood.
Current treatment options include a bone marrow transplant which is limited by available donors and graft versus host disease and immune suppressive drugs that are only partially effective. Dr. Rosa Bacchetta and her team at Stanford will use gene therapy to insert a normal version of the FOXP3 gene into the patient’s own T Cells to restore the normal function of regulatory T Cells.
This approach has already been accorded an orphan drug and rare pediatric disease designation by the FDA (we blogged about it last year)
Orphan drug designation is a special status given by the Food and Drug Administration (FDA) for potential treatments of rare diseases that affect fewer than 200,000 in the U.S. This type of status can significantly help advance treatments for rare diseases by providing financial incentives in the form of tax credits towards the cost of clinical trials and prescription drug user fee waivers.
Under the FDA’s rare pediatric disease designation program, the FDA may grant priority review to Dr. Bacchetta if this treatment eventually receives FDA approval. The FDA defines a rare pediatric disease as a serious or life-threatening disease in which the serious or life-threatening manifestations primarily affect individuals aged from birth to 18 years and affects fewer than 200,000 people in the U.S.
Congratulations to the team and we wish them luck as they begin the trial.
Someone who needs no introduction to regular readers of this blog is UCLA’s Dr. Don Kohn. A recent study in the New England Journal of Medicine highlighted how his work in developing a treatment for severe combined immune deficiency (SCID) has helped save the lives of dozens of children.
Now a new study in the journal Blood shows that those benefits are long-lasting, with 90% of patients who received the treatment eight to 11 years ago still disease-free.
In a news release Dr. Kohn said: “What we saw in the first few years was that this therapy worked, and now we’re able to say that it not only works, but it works for more than 10 years. We hope someday we’ll be able to say that these results last for 80 years.”
Ten children received the treatment between 2009 and 2012. Nine were babies or very young children, one was 15 years old at the time. That teenager was the only one who didn’t see their immune system restored. Dr. Kohn says this suggests that the therapy is most effective in younger children.
Dr. Kohn has since modified the approach his team uses and has seen even more impressive and, we hope, equally long-lasting results.
The second Wednesday in October is celebrated as Stem Cell Awareness Day. It’s an event that CIRM has been part of since then Governor Arnold Schwarzenegger launched it back in 2008 saying: ”The discoveries being made today in our Golden State will have a great impact on many around the world for generations to come.”
In the past we would have helped coordinate presentations by scientists in schools and participated in public events. COVID of course has changed all that. So, this year, to help mark the occasion we asked some people who have been in the forefront of making Governor Schwarzenegger’s statement come true, to share their thoughts and feelings about the day. Here’s what they had to say.
What do you think is the biggest achievement so far in stem cell research?
Jan Nolta, PhD., Director of the Stem Cell Program at UC Davis School of Medicine, and directs the new Institute for Regenerative Cures. “The work of Don Kohn and his UCLA colleagues and team members throughout the years- developing stem cell gene therapy cures for over 50 children with Bubble baby disease. I was very fortunate to work with Don for the first 15 years of my career and know that development of these cures was guided by his passion to help his patients.
When people ask you what kind of impact CIRM and stem cell research has had on your life what do you say?
Pawash Priyank and Upasana Thakur, parents of Ronnie,who was born with a life-threatening immune disorder but is thriving today thanks to a CIRM-funded clinical trial at UC San Francisco. “This is beyond just a few words and sentences but we will give it a shot. We are living happily today seeing Ronnie explore the world day by day, and this is only because of what CIRM does every day and what Stem cell research has done to humanity. Researchers and scientists come up with innovative ideas almost every day around the globe but unless those ideas are funded or brought to implementation in any manner, they are just in the minds of those researchers and would never be useful for humanity in any manner. CIRM has been that source to bring those ideas to the table, provide facilities and mechanisms to get those actually implemented which eventually makes babies like Ronnie survive and see the world. That’s the impact CIRM has. We have witnessed and heard several good arguments back in India in several forums which could make difference in the world in different sectors of lives but those ideas never come to light because of the lack of organizations like CIRM, lack of interest from people running the government. An organization like CIRM and the interest of the government to fund them with an interest in science and technology actually changes the lives of people when some of those ideas come to see the light of real implementation.
What are your biggest hopes for the future at UC Davis?
Jan Nolta, PhD: “The future of stem cell and gene therapy research is very bright at UC Davis, thanks to CIRM and our outstanding leadership. We currently have 48 clinical trials ongoing in this field, with over 20 in the pipeline, and are developing a new education and technology complex, Aggie Square, next to the Institute for Regenerative Cures, where our program is housed. We are committed to our very diverse patient population throughout the Sacramento region and Northern California, and to expanding and increasing the number of novel therapies that can be brought to all patients who need them.”
What are your biggest hopes for the future at Cedars-Sinai?
Clive Svendsen, PhD: “That young investigators will get CIRM or NIH funding and be leaders in the regenerative medicine field.”
What do you hope is the future for stem cell research?
Pawash Priyank and Upasana Thakur: “We always have felt good about stem cell therapy. For us, a stem cell has transformed our lives completely. The correction of sequencing in the DNA taken out of Ronnie and injecting back in him has given him life. It has given him the immune system to fight infections. Seeing him grow without fear of doing anything, or going anywhere gives us so much happiness every hour. That’s the impact of stem cell research. With right minds continuing to research further in stem cell therapy bounded by certain good processes & laws around (so that misuse of the therapy couldn’t be done) will certainly change the way treatments are done for certain incurable diseases. I certainly see a bright future for stem cell research.”
On a personal note what is the moment that touched you the most in this journey.
Jan Nolta, PhD: “Each day a new patient or their story touches my heart. They are our inspiration for working hard to bring new options to their care through cell and gene therapy.”
Clive Svendsen, PhD: “When I realized we would get the funding to try and treat ALS with stem cells”
How important is it to raise awareness about stem cell research and to educate the next generation about it?
Pawash Priyank and Upasana Thakur: “Implementing stem cell therapy as a curriculum in the educational systems right from the beginning of middle school and higher could prevent false propaganda of it through social media. Awareness among people with accurate articles right from the beginning of their education is really important. This will also encourage the new generation to choose this as a subject in their higher studies and contribute towards more research to bring more solutions for a variety of diseases popping up every day.”
World Mental Health Day is observed on 10 October every year. It’s a time to try and raise awareness about mental health issues and the impact they have not just on the individual but their family, their community and all of us. The theme for World Mental Health Day 2021 is ‘mental health in an unequal world.’
To highlight the issues raised on World Mental Health Day we talked to one of CIRM’s newest Board member, Dr. Le Ondra Clark Harvey. She’s a psychologist and the CEO of the California Council of Community Behavioral Health Agencies (CCCBHA) a statewide advocacy organization representing mental health and substance use disorder non-profit agencies that collectively serve over 750 thousand Californians annually.
What made you want to be on the CIRM Board?
I was recommended to apply for the CIRM Board by a member of CCCBHA, the organization I am privileged to lead and serve. I saw the position as an opportunity to shed light on cognitive disorders that many do not readily think of when they think about stem cell research. The appointment also has personal meaning to me as I have a grandfather who is a cancer survivor and who has an Alzheimer’s diagnosis. Breast cancer has also affected women in my family, including myself, and I know that the research that CIRM funds can assist with finding a cure and providing accessible treatment options for all Californians.
A lot of people might not think that stem cells would have a role in addressing mental health issues, what role do you think they can play?
You are correct, most people do not immediately think of stem cell therapies as a remedy to brain health disorders. However, there are many cognitive disorders and symptoms that can be mitigated, and hopefully someday ameliorated, as a result of stem cell therapies. For example, autism and other developmental disabilities, dementia, Alzheimer’s, Tourette’s and tardive dyskinesia.
What are the biggest challenges we face in addressing mental health issues in this country?
Stigma remains a significant barrier that impacts the ability to provide – particularly among racially and ethnically diverse communities. In my own practice, I’ve seen how stigma can prevent individuals from entering into care even when access issues have been mitigated. Public awareness campaigns, and culturally specific advocacy efforts and practices must be integrated into treatment models in order to provide individuals with the specific care they need.
Do you think that the widespread media attention paid to Naomi Osaka and Simone Biles has helped raise awareness about mental health and perhaps also reduced some of the stigma surrounding it?
Yes, I do. Also, the pandemic has opened many individuals eyes, and engendered a sense of empathy, about the prevalence and impact that isolation and loneliness can have on a person.
Human embryonic stem cells (hESCs) have many remarkable properties, not the least of which is their ability to turn into every other kind of cell in our body. But there are limits to what researchers can do with embryonic stem cells. One issue is that there aren’t always hESCs available – they come from eggs donated by couples who have undergone in vitro fertilization. Another is that researchers can only develop these cells in the laboratory for 14 days (though that rule may be changing).
Now researchers at Caltech have developed a kind of hESC-in-a-dish that could help make it easier to answer questions about human development without the need to wait for a new line of hESCs.
The team, led by Magdalena Zernicka-Goetz, used a line of expanded pluripotent cells (EPSCs), originally derived from a human embryo, to create a kind of 3D model that mimics some of the activities of an embryo.
The cool thing about these cells is that, because they were originally derived from an embryo, they retain some “memory” of how they are supposed to work. In a news release Zernicka-Goetz says this enables them to display elements of both polarization and cavitation, early crucial phases in the development of a human embryo.
“The ability to assemble the basic structure of the embryo seems to be a built-in property of these earliest embryonic cells that they are simply unable to ‘forget.’ Nevertheless, either their memory is not absolutely precise or we don’t yet have the best method of helping the cells recover their memories. We still have further work to do before we can get human stem cells to achieve the developmental accuracy that is possible with their equivalent mouse stem cell counterparts.”
Being able to create these embryo-like elements means researchers can generate cells in large numbers and won’t be so dependent on donated embryos.
In the study, published in the journal Nature Communications, the researchers say this could help them develop a deeper understanding of embryonic development.
“Understanding human development is of fundamental biological and clinical importance. Despite its significance, mechanisms behind human embryogenesis remain largely unknown…. this stem cell platform provides insights into the design of stem cell models of embryogenesis.
If you have read the headlines lately, you’ll know that the COVID-19 pandemic is having a huge impact on the shipping industry. Container vessels are forced to sit out at anchor for a week or more because there just aren’t enough dock workers to unload the boats. It’s a simple rule of economics, you can have all the demand you want but if you don’t have the people to help deliver on the supply side, you are in trouble.
The same is true in regenerative medicine. The field is expanding rapidly and that’s creating a rising demand for skilled workers to help keep up. That doesn’t just mean scientists, but also technicians and other skilled individuals who can ensure that our ability to manufacture and deliver these new therapies is not slowed down.
That’s one of the reasons why CIRM has been a big supporter of training programs ever since we were created by the voters of California when they approved Proposition 71. And now we are kick-starting those programs again to ensure the field has all the talented workers it needs.
Last week the CIRM Board approved 18 programs, investing more than $86 million, as part of the Agency’s Research Training Grants program. The goal of the program is to create a diverse group of scientists with the knowledge and skill to lead effective stem cell research programs.
The awards provide up to $5 million per institution, for a maximum of 20 institutions, over five years, to support the training of predoctoral graduate students, postdoctoral trainees, and/or clinical trainees.
This is a revival of an earlier Research Training program that ran from 2006-2016 and trained 940 “CIRM Scholars” including:
• 321 PhD students • 453 Postdocs • 166 MDs
These grants went to academic institutions from UC Davis in Sacramento to UC San Diego down south and everywhere in-between. A 2013 survey of the students found that most went on to careers in the industry.
56% continued to further training
14% advanced to an academic research faculty position
10.5% advanced to a biotech/industry position
12% advanced to a non-research position such as teaching, medical practice, or foundation/government work
The Research Training Grants go to:
CIRM Training Program in Translational Regenerative Medicine
TRANSCEND – Training Program to Advance Interdisciplinary Stem Cell Research, Education, and Workforce Diversity
UC Los Angeles
UCLA Training Program in Stem Cell Biology
University of Southern California
Training Program Bridging Stem Cell Research with Clinical Applications in Regenerative Medicine
UC Santa Cruz
CIRM Training Program in Systems Biology of Stem Cells
CIRM Regenerative Medicine Research Training Program
City of Hope
Research Training Program in Stem Cell Biology and Regenerative Medicine
CIRM Scholar Training Program
Training the Next Generation of Biologists and Engineers for Regenerative Medicine
CIRM Cell and Gene Therapy Training Program 2.0
Children’s Hospital of Los Angeles
CIRM Training Program for Stem Cell and Regenerative Medicine Research
UC San Diego
Interdisciplinary Stem Cell Training Grant at UCSD III
Training Scholars in Regenerative Medicine and Stem Cell Research
UC San Francisco
Scholars Research Training Program in Regenerative Medicine, Gene Therapy, and Stem Cell Research
A Multidisciplinary Stem Cell Training Program at Sanford Burnham Prebys Institute, A Critical Component of the La Jolla Mesa Educational Network
UC Santa Barbara
CIRM Training Program in Stem Cell Biology and Engineering
CIRM Scholars Comprehensive Research Training Program
Lundquist Institute for Biomedical Innovation
Stem Cell Training Program at the Lundquist Institute
These are not the only awards we make to support training the next generation of scientists. We also have our SPARK and Bridges to Stem Cell Research programs. The SPARK awards are for high school students, and the Bridges program for graduate or Master’s level students.
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.
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.