The brain is a complex part of the human body that allows for the formation of thoughts and consciousness. In many ways it is the essence of who we are as individuals. Because of its importance, our bodies have developed various layers of protection around this vital organ, one of which is called the blood-brain barrier (BBB).
The BBB is a thin border of various cell types around the brain that regulate what can enter the brain tissue through the bloodstream. Its primary purpose is to prevent toxins and other unwanted substances from entering the brain and damaging it. Unfortunately this barrier can also prevent helpful medications, designed to fix problems, from reaching the brain.
Several brain disorders, such as Amyotrophic Lateral Sclerosis (ALS – also known as Lou Gehrig’s disease), Parkinson’s Disease (PD), and Huntington’s Disease (HD) have been linked to defective BBBs that keep out critical biomolecules needed for healthy brain activity.
In a CIRM-funded study, a team at Cedars-Sinai Medical Center created a BBB through the use of stem cells and an Organ-Chip made from induced pluripotent stem cells (iPSCs). These are a specific type of stem cells that can turn into any type of cell in the body and can be generated from a person’s own cells. In this study, iPSCs were created from adult blood samples and used to make the neurons and other supporting cells that make up the BBB. These cells were then placed inside an Organ-Chip which recreates the environment that cells normally experience within the human body.
Inside the 3-D Organ-Chip, the cells were able to form a BBB that functions as it does in the body, with the ability to block entry of certain drugs. Most notably, when the BBB was generated from cell samples of patients with HD, the BBB malfunctioned in the same way that it does in patients with the disease.
These findings expand the potential for personalized medicine for various brain disorders linked to problems in the BBB. In a press release, Dr. Clive Svendsen, director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute and senior author of the study, was quoted as saying,
“The study’s findings open a promising pathway for precision medicine. The possibility of using a patient-specific, multicellular model of a blood barrier on a chip represents a new standard for developing predictive, personalized medicine.”
The full results of the study were published in the scientific journal Cell Stem Cell.
Understanding the basic biology of how a cell functions can be crucial to being able to better understand a disease and unlock a potential approach for a treatment. Stem cells are unique in that they give scientists the opportunity to create a controlled environment of cells that might be otherwise difficult to study. Dr. Eva Hedlund and a team of researchers at the Karolinska Institute in Sweden utilize a stem cell model approach to uncover findings related to Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s Disease.
ALS is a progressive neurodegenerative disease that destroys motor neurons, a type of nerve cell, that are important for voluntary muscle movement. When motor neurons can no longer send signals to the muscles, the muscles begin to deteriorate, a process formally known as atrophy. The progressive atrophy leads to muscle paralysis, including those in the legs and feet, arms and hands, and those that control swallowing and breathing. It affects about 30,000 people in the United States alone, with 5,000 new cases diagnosed each year. There is currently no cure.
In a previous study, researchers at the Karolinska Institute were able to successfully create oculomotor neurons from embryonic stem cells. For reasons not yet fully understood, oculomotor neurons are “ALS resilient” and can survive all stages of the disease.
In the current study, published in Stem Cell Reports, Dr. Hedlund and her team found that the oculomotor neurons they generated appeared more resilient to ALS-like degeneration when compared to spinal cord motor neurons, something commonly observed in humans. Furthermore, they discovered that their “ALS resilient” neurons generated from stem cells activate a survival-enhancing signal known as Akt, which is common in oculomotor neurons in humans and could explain their resilience. These results could potentially aid in identifying genetic targets for treatments protecting sensitive neurons from the disease.
From Day One CIRM’s goal has been to advance stem cell research in California. We don’t do that just by funding the most promising research -though the 51 clinical trials we have funded to date clearly shows we do that rather well – but also by trying to bring the best minds in the field together to overcome problems.
Over the years we
have held conferences, workshops and symposiums on everything from Parkinson’s
palsy and tissue
engineering. Each one attracted the key players and stakeholders in the
field, brainstorming ideas to get past obstacles and to explore new ways of
developing therapies. It’s an attempt to get scientists, who would normally be
rivals or competitors, to collaborate and partner together in finding the best
It’s not easy to do,
and the results are not always obvious right away, but it is essential if we
hope to live up to our mission of accelerating stem cell therapies to patients
with unmet medical needs.
For example. This
past week we helped organize two big events and were participants in another.
The first event we
pulled together, in partnership with Cedars-Sinai Medical Center, was a
workshop called “Brainstorm Neurodegeneration”. It brought together leaders in stem
cell research, genomics, big data, patient advocacy and the Food and Drug
Administration (FDA) to tackle some of the issues that have hampered progress
in finding treatments for things like Parkinson’s, Alzheimer’s, ALS and
ambitiously subtitled the workshop “a cutting-edge meeting to disrupt the field”
and while the two days of discussions didn’t resolve all the problems facing us
it did produce some fascinating ideas and some tantalizing glimpses at ways to
advance the field.
Two days later we partnered with UC San Francisco to host the Fourth Annual CIRM Alpha Stem Cell Clinics Network Symposium. This brought together the scientists who develop therapies, the doctors and nurses who deliver them, and the patients who are in need of them. The theme was “The Past, Present & Future of Regenerative Medicine” and included both a look at the initial discoveries in gene therapy that led us to where we are now as well as a look to the future when cellular therapies, we believe, will become a routine option for patients.
different groups together is important for us. We feel each has a key role to
play in moving these projects and out of the lab and into clinical trials and
that it is only by working together that they can succeed in producing the
treatments and cures patients so desperately need.
As always it was the patients who surprised us. One, Cierra Danielle Jackson, talked about what it was like to be cured of her sickle cell disease. I think it’s fair to say that most in the audience expected Cierra to talk about her delight at no longer having the crippling and life-threatening condition. And she did. But she also talked about how hard it was adjusting to this new reality.
Cierra said sickle
cell disease had been a part of her life for all her life, it shaped her daily
life and her relationships with her family and many others. So, to suddenly
have that no longer be a part of her caused a kind of identity crisis. Who was
she now that she was no longer someone with sickle cell disease?
She talked about how
people with most diseases were normal before they got sick, and will be normal
after they are cured. But for people with sickle cell, being sick is all they
have known. That was their normal. And now they have to adjust to a new normal.
It was a powerful
reminder to everyone that in developing new treatments we have to consider the
whole person, their psychological and emotional sides as well as the physical.
And so on to the third event we were part of, the Stanford Drug Discovery Symposium. This was a high level, invitation-only scientific meeting that included some heavy hitters – such as Nobel Prize winners Paul Berg and Randy Schekman, former FDA Commissioner Robert Califf. Over the course of two days they examined the role that philanthropy plays in advancing research, the increasingly important role of immunotherapy in battling diseases like cancer and how tools such as artificial intelligence and big data are shaping the future.
CIRM’s President and CEO, Dr. Maria Millan, was one of those invited to speak and she talked about how California’s investment in stem cell research is delivering Something Better than Hope – which by a happy coincidence is the title of our 2018 Annual Report. She highlighted some of the 51 clinical trials we have funded, and the lives that have been changed and saved by this research.
The presentations at
these conferences and workshops are important, but so too are the conversations
that happen outside the auditorium, over lunch or at coffee. Many great
collaborations have happened when scientists get a chance to share ideas, or
when researchers talk to patients about their ideas for a successful clinical
It’s amazing what happens when you bring people together who might otherwise never have met. The ideas they come up with can change the world.
There are limitations to studying cells under a microscope. To understand some of the more complex processes, it is critical to see how these cells behave in an environment that is similar to conditions in the body. The production of organoids has revolutionized this approach.
Organoids are three-dimensional structures derived from stem cells that have similar characteristics of an actual organ. There have been several studies recently published that have used this approach to understand a wide scope of different areas.
In one such instance, researchers at The University of Cambridge were able to grow a “mini-brain” from human stem cells. To demonstrate that this organoid had functional capabilities similar to that of an actual brain, the researchers hooked it up to a mouse spinal cord and surrounding muscle. What they found was remarkable– the “mini-brain” sent electrial signals to the spinal cord that made the surrounding muscles twitch. This model could pave the way for studying neurodegenerative diseases such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS).
Speaking of SMA, researchers in Singapore have used organoids to come up with some findings that might be able to help people battling the condition.
SMA is a neurodegenerative disease caused by a protein
deficiency that results in nerve degeneration, paralysis and even premature
death. The fact that it mainly affects children makes it even worse. Not much
is known how SMA develops and even less how to treat or prevent it.
That’s where the research from the A*STAR’s Institute of
Molecular and Cell Biology (IMCB) comes in. Using the iPSC method
they turned tissue samples from healthy people and people with SMA into spinal
They then compared the way the cells
developed in the organoids and found that the motor nerve cells from healthy
people were fully formed by day 35. However, the cells from people with SMA
started to degenerate before they got to that point.
They also found that the protein
problem that causes SMA to develop did so by causing the motor nerve cells to
divide, something they don’t normally do. So, by blocking the mechanism that
caused the cells to divide they were able to prevent the cells from dying.
“We are one of the first labs to report the formation of spinal organoids. Our study presents a new method for culturing human spinal-cord-like tissues that could be crucial for future research.”
Just yesterday the CIRM Board awarded almost $4 million to Ankasa Regenerative Therapeutics to try and develop a treatment for another debilitating back problem called degenerative spondylolisthesis.
And finally, organoid modeling was used to better understand and study an infectious disease. Scientists from the Max Planck Institute for Infection Biology in Berlin created fallopian tube organoids from normal human cells. Fallopian tubes are the pair of tubes found inside women along which the eggs travel from the ovaries to the uterus. The scientists observed the effects of chronic infections of Chlamydia, a sexually transmittable infection. It was discovered that chronic infections lead to permanent changes at the DNA level as the cells age. These changes to DNA are permanent even after the infection is cleared, and could be indicative of the increased risk of cervical cancer observed in women with Chlamydia or those that have contracted it in the past.
It’s hard thinking of something as rare when one in 20 people are at risk of experiencing it in their lifetime. But that’s the situation with rare diseases. There are more than 7,000 of them and each affects under 200,000 people. In some cases they may only affect a few hundred people. But for each person that disease, though rare, poses a real threat. And that’s why Rare Disease Day was created.
Rare Disease Day is held on the last day of February each year. The goal is to raise awareness among the general public about the huge impact these diseases have on people’s lives. That impact is not just on the person with the disease but on the whole family who are often struggling just to get a diagnosis.
Every year groups around the world, from patients and patient advocacy organizations to researchers and policymakers, stage events to mark the day. This year there are more than 460 events being held in 96 countries, everywhere from Albania and Andora to Tunisia and Uruguay.
Here in the US many groups organize events at State Capitols
to educate elected officials and policy makers about the particular needs of
these communities and the promise that scientific
research holds to combat these conditions. Others have auctions to raise
funds for research or public debates to raise awareness.
Each event is unique in its own way because each represents many different diseases, many different needs, and many different stories. The goal of these events is to put a human face on each condition, to give it visibility, so that it is no longer something most people have never heard of, instead it becomes something that affects someone you may know or who reminds you of someone you know.
Here’s a video from Spain that does just that.
You can find a complete list of events being held around the
world to mark Rare
At CIRM we feel a special link to this day. That’s because many of the diseases we fund research into are rare diseases such as severe combined immunodeficiency (SCID), and ALS or Lou Gehrig’s disease, and Sickle Cell Disease.
These diseases affect relatively small numbers of patients so they often struggle to get funding for research. Because we do not have to worry about making a profit on any therapy we help develop we can focus our efforts on supporting those with unmet medical needs. And it’s paying off. Our support has already helped develop a therapy for SCID that has cured 40 children. We have two clinical trials underway for ALS or Lou Gehrig’s disease. We also have two clinical trials for Sickle Cell Disease and have reached a milestone agreement with the National Heart, Lung and Blood Institute (NHLBI) on a partnership to help develop a cure for this crippling and life-threatening disorder.
The hope is that events like Rare Disease Day let people
know that even though they have a condition that affects very few, that they
are not alone, but that they are part of a wider, global community, a community
committed to working to find treatments and cures for all of them.
Clive Svendsen, PhD, left, director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute, and Samuel Sances, PhD, a postdoctoral fellow at the institute, with the January 2019 special edition of National Geographic. The magazine cover features a striking image of spinal cord tissue that was shot by Sances in his lab. Photo by Cedars-Sinai.
National Geographic is one of those iconic magazines that everyone knows about but few people read. Which is a shame, because it’s been around since 1888 and has helped make generations of readers aware about the world around them. And now, it’s shifting gears and helping people know more about the world inside them. That’s because a special January edition of National Geographic highlights stem cells.
The issue, called ‘The Future of Medicine’, covers a wide range of issues including stem cell research being done at Cedars-Sinai by Clive Svendsen and his team (CIRM is funding Dr. Svendsen’s work in a clinical trial targeting ALS, you can read about that here). The team is using stem cells and so-called Organ-Chips to develop personalized treatments for individual patients.
Here’s how it works. Scientists take blood or skin cells from individual patients, then using the iPSC method, turn those into the kind of cell in the body that is diseased or damaged. Those cells are then placed inside a device the size of an AA battery where they can be tested against lots of different drugs or compounds to see which ones might help treat that particular problem.
This approach is still in the development phase but if it works it would enable doctors to tailor a treatment to a patient’s specific DNA profile, reducing the risk of complications and, hopefully, increasing the risk it will be successful. Dr. Svendsen says it may sound like science fiction, but this is not far away from being science fact.
“I think we’re entering a new era of medicine—precision medicine. In the future, you’ll have your iPSC line made, generate the cell type in your body that is sick and put it on a chip to understand more about how to treat your disease.”
Dr. Svendsen isn’t the only connection CIRM has to the article. The cover photo for the issue was taken by Sam Sances, PhD, who received a CIRM stem cell research scholarship in 2010-2011. Sam says he’s grateful to CIRM for being a longtime supporter of his work. But then why wouldn’t we be. Sam – who is still just 31 years old – is clearly someone to watch. He got his first research job, as an experimental coordinator, with Pacific Ag Research in San Luis Obispo when he was still in high school.
You never know when you write something if people are going to read it. Sometimes you wonder if anyone is going to read it. So, it’s always fun, and educational, to look back at the end of the year and see which pieces got the most eyeballs.
It isn’t always the ones you think will draw the biggest audiences. Sometimes it is diseases that are considered “rare” (those affecting fewer than 200,000 people) that get the most attention.
Maybe it’s because those diseases have such a powerful online community which shares news, any news, about their condition of interest with everyone they know. Whatever the reason, we are always delighted to share encouraging news about research we are funding or encouraging research that someone else is funding.
That was certainly the case with the top two stories this year. Both were related to ALS or Lou Gehrig’s disease. It’s a particularly nasty condition. People diagnosed with ALS have a life expectancy of just 2 to 5 years. So it’s probably not a big surprise that stories suggesting stem cells could expand that life span got a big reception.
Whatever the reason, we’re just happy to share hopeful news with everyone who comes to our blog.
And so, without further ado, here is the list of the most popular Stem Cellar Blog Posts for 2018.
All of us in the Communications team at CIRM consider it an honor and privilege to be able to work here and to meet many of the people behind these stories; the researchers and the patients and patient advocates. They are an extraordinary group of individuals who help remind us why we do this work and why it is important. We love our work and we hope you enjoy it too. We plan to be every bit as active and engaged in 2019.
Proposition 71 is the state ballot initiative that created California’s Stem Cell Agency. This month, the Agency reached another milestone when the 71st clinical trial was initiated in the CIRM Alpha Stem Cell Clinics (ASCC) Network. The ASCC Network deploys specialized teams of doctors, nurses and laboratory technicians to conduct stem cell clinical trials at leading California Medical Centers.
These teams work with academic and industry partners to support patient-centered for over 40 distinct diseases including:
Amyotrophic Lateral Sclerosis (ALS)
Brain Injury & Stroke
Cancer at Multiple Sites
Diabetes Type 1
Eye Disease / Blindness Heart Failure
HIV / AIDS
Severe Combined Immunodeficiency (SCID)
Sickle Cell Anemia
Spinal Cord Injury
These clinical trials have treated over 400 patients and counting. The Alpha Stem Cell Clinics are part of CIRM’s Strategic Infrastructure. The Strategic Infrastructure program which was developed to support the growth of stem cell / regenerative medicine in California. A comprehensive update of CIRM’s Infrastructure Program was provided to our Board, the ICOC.
CIRM’s infrastructure catalyzes stem cell / regenerative medicine by providing resources to all qualified researchers and organizations requiring specialized expertise. For example, the Alpha Clinics Network is supporting clinical trials from around the world.
Many of these trials are sponsored by commercial companies that have no CIRM funding. To date, the ASCC Network has over $27 million in contracts with outside sponsors. These contracts serve to leverage CIRMs investment and provide the Network’s medical centers with a diverse portfolio of clinical trials to address patients’’ unmet medical needs.
Alpha Clinics – Key Performance Metrics
70+ Clinical Trials
400+ Patients Treated
40+ Disease Indications
Over $27 million in contracts with commercial sponsors
The CIRM Alpha Stem Cell Clinics and broader Infrastructure Programs are supporting stem cell research and regenerative medicine at every level, from laboratory research to product manufacturing to delivery to patients. This infrastructure has emerged to make California the world leader in regenerative medicine. It all started because California’s residents supported a ballot measure and today we have 71 clinical trials for 71.
The following article is an Op Ed that appeared in today’s print version of the San Francisco Chronicle
Biotechnology was born in California in the 1970s based on the discovery out of one of its universities and California is responsible for an industry that has impacted the lives of billions of people worldwide. In 2004, the voters of California approved Proposition 71, creating the California Institute for Regenerative Medicine and setting the state on the path to becoming a global leader in stem cell research. Today the therapies resulting from the institute’s work are not just changing lives, they are already saving lives.
Lives like Evie Vaccaro, who is alive today because of a treatment CIRM is funding. Vaccaro was born with SCID, also known as “bubble baby disease,” an immune disorder that often kills babies in their first two years. Vaccaro and dozens of other babies were given stem cell treatments thanks to the institute. All are showing improvement; some are now several years past treatment and considered cured.
An accident left Jake Javier from Danville paralyzed from the chest down on the eve of his high school graduation. Javier was treated in a CIRM-funded clinical trial. Today he has regained the use of his arms and hands, is driving a car and is a sophomore at Cal Poly San Luis Obispo. Five other patients treated at the same time as Javier have all experienced improvements meaning that instead of needing round-the-clock care, they can lead independent lives.
A study by the Tufts Center for the Study of Drug Development estimated it takes at least 10 years and $2.6 billion to develop one successful drug. In 14 years, and with just $3 billion, CIRM has funded 1,000 different projects, enrolled 900 patients, and supported 49 different clinical trials targeting diseases such as cancer, kidney failure and leukemia. Four of these programs have received an expedited designation by the U.S. Food and Drug Administration, meaning they could get faster approval to help more patients
We have created a network of world class medical clinics that have expertise in delivering treatments to patients. The CIRM Alpha Clinics offer treatments based on solid science, unlike the unlicensed clinics sprouting up around California that peddle unproven and potentially harmful therapies that cost patients thousands of dollars.
Supported the creation of 12 stem-cell research facilities in California
Attracted hundreds of top-tier researchers to California
Trained a new generation of stem-cell scientists
Brought clinical trials to California — for example, one targeting ALS or Lou Gehrig’s disease
Deployed rigorous scientific standards and support so our programs have a “seal of approval” to attract $2.7 billion in additional investments from industry and other sources.
We recently have partnered with the National Institutes of Health to break down barriers and speed up the approval process to bring curative treatments to patients with Sickle Cell Disease.
Have we achieved all we wanted to? Of course not. The first decade of CIRM’s life was laying the groundwork, developing the knowledge and expertise and refining processes so that we can truly accelerate progress. As a leader in this burgeoning field of regenerative medicine, CIRM needs to continue its mission of accelerating stem-cell treatments to patients with unmet medical needs.
Dr. Maria T. Millan is President and CEO and Jonathan Thomas, JD, PhD, is the Board Chairman of the California Institute of Regenerative Medicine.
Imagine being told that you have a condition that gradually causes you to lose the ability to control your body movements, from picking up a pencil to walking to even breathing. Such is the reality for the nearly 6,000 people who are diagnosed with amyotrophic lateral sclerosis (ALS) every year, in the United States alone.
ALS, also known as Lou Gehrig’s disease, is a neurodegenerative disease that causes the degradation of motor neurons, or nerves that are responsible for all voluntary muscle movements, like the ones mentioned above. It is a truly devastating disease with a particularly poor prognosis of two to five years from the time of diagnosis to death. There are only two approved drugs for ALS and these do not stop it but only slow progression of the disease; and even then only for some patients, not all.
Two small Phase I clinical trials detailed in Cell Journal demonstrated that injecting mesenchymal stem cells (MSCs), derived from the patient’s own bone marrow, was safe when administered via injection into the bloodstream or the spinal cord. Previous studies had shown that MSCs both revived motor neurons and extended the lifespan in a rodent model of the disease.
In humans, many studies have shown that MSCs taken from bone marrow are safe for use in humans, but these studies have disagreed about whether injection via the bloodstream or spinal cord route is the most effective way to deliver the therapy. This report confirms that both routes of administration are safe as no adverse clinical events were observed for either group throughout the study time frame.
While an important stepping stone, there is still a long way to go. For example, while no adverse clinical events were observed in either group, the overall ALS-FRS score, a clinical scale to determine ALS disease progression, worsened in all patients over the course of the study. Whether this was just due to natural progression of the disease, or because of the stem cell treatment is difficult to determine given the small size of the cohort.
One reason the scientists suggest that could explain the disease decline is because the MSCs were taken from the ALS patients themselves, which means these cells were likely not functioning optimally prior to re-introduction into the patient. To remedy this, they hope to test the effect of MSCs taken from healthy donors in both injection routes in the future. They also need a larger cohort of patients to determine whether or not there is a difference in the therapeutic effect of administering stem cells via the two different routes.
While it may seem that the results from this clinical trial are not particularly groundbreaking or innovative, it is important to remember that these incremental improvements through clinical trials are critical for bringing safe and effective therapies to the market. For more information on the different phases of clinical trials, please refer to this video.