It’s not often you get a chance to hear some of the brightest minds around talk about their stem cell research and what it could mean for you, me and everyone else. That’s why we’re delighted to be bringing some of the sharpest tools in the stem cell shed together in one – virtual – place for our CIRM 2020 Grantee Meeting.
The event is Monday September 14th and Tuesday September 15th. It’s open to anyone who wants to attend and, of course, it’s all being held online so you can watch from the comfort of your own living room, or garden, or wherever you like. And, of course, it’s free.
Dr. Daniela Bota, UC Irvine
The list of speakers is a Who’s Who of researchers that CIRM has funded and who also happen to be among the leaders in the field. Not surprising as California is a global center for regenerative medicine. And you will of course be able to post questions for them to answer.
Dr. Deepak Srivastava, Gladstone Institutes
The key speakers include:
Larry Goldstein: the founder and director of the UCSD Stem Cell Program talking about Alzheimer’s research
Irv Weissman: Stanford University talking about anti-cancer therapies
Other topics include the latest stem cell approaches to COVID-19, spinal cord injury, blindness, Parkinson’s disease, immune disorders, spina bifida and other pediatric disorders.
You can choose one topic or come both days for all the sessions. To see the agenda for each day click here. Just one side note, this is still a work in progress so some of the sessions have not been finalized yet.
And when you are ready to register go to our Eventbrite page. It’s simple, it’s fast and it will guarantee you’ll be able to be part of this event.
For years CIRM and others in the stem cell community (hello Paul Knoepfler) have been warning people about the dangers of going to clinics offering unproven and unapproved stem cell therapies. Recently the drum beat of people and organizations coming out in support of that stand has grown louder and louder. Mainstream media – TV and print – have run articles about these predatory clinics. And now, Google has joined those ranks, announcing it will restrict ads promoting these clinics.
“We regularly review and revise our
advertising policies. Today, we’re announcing a new Healthcare and
medicines policy to prohibit advertising for unproven or experimental
medical techniques such as most stem cell therapy, cellular (non-stem) therapy,
and gene therapy.”
“Google’s new policy banning
advertising for speculative medicines is a much-needed and welcome step to curb
the marketing of unscrupulous medical products such as unproven stem cell
therapies. While stem cells have great potential to help us understand and
treat a wide range of diseases, most stem cell interventions remain
experimental and should only be offered to patients through well-regulated
clinical trials. The premature marketing and commercialization of unproven stem
cell products threatens public health, their confidence in biomedical research,
and undermines the development of legitimate new therapies.”
Speaking of Deepak – we can use first
names here because we are not only great admirers of him as a physician but also
as a researcher, which is why we have funded
some of his research – he has just published a wonderfully well written
article criticizing these predatory clinics.
The article – in Scientific
American – is titled “Don’t Believe Everything You Hear About Stem Cells”
and rather than paraphrase his prose, I think it best if you read it yourself.
So, here it is.
Don’t Believe Everything You Hear about Stem Cells
The science is progressing rapidly,but bad
actors have co-opted stem cells’ hope and promise by preying on unsuspecting
patients and their families
Stem cell science is moving forward
rapidly, with potential therapies to treat intractable human diseases on the
horizon.Clinical trials are now underway to test the safety
and effectiveness of stem cell–based treatments for blindness,spinal
cord injury,heart disease,Parkinson’s
disease, and more,some with early positive results.A
sense of urgency drives the scientific community, and there is tremendous hope
to finally cure diseases that, to date, have had no treatment.
But don’t believe everything you hear about stem cells. Advertisements and pseudo news articles promote stem cell treatments for everything from Alzheimer’s disease,autism and ALS, to cerebral palsy and other diseases.The claims simply aren’t true–they’re propagated by people wanting to make money off of a desperate and unsuspecting or unknowing public.Patients and their families can be misled by deceptive marketing from unqualified physicians who often don’t have appropriate medical credentials and offer no scientific evidence of their claims.In many cases, the cells being utilized are not even true stem cells.
Advertisements for stem cell treatments are showing up everywhere, with too-good-to-be-true
claims and often a testimonial or two meant to suggest legitimacy or efficacy.Beware of the following:
• Claims that stem
cell treatments can treat a wide range of diseases using a singular stem cell
type. This is unlikely to be true.
• Claims that stem
cells taken from one area of the body can be used to treat another, unrelated
area of the body. This is also unlikely to be true.
• Patient testimonials used to validate a
particular treatment, with no scientific evidence. This is a red flag.
• Claims that
evidence doesn’t yet exist because the clinic is running a patient-funded
trial. This is a red flag; clinical trials rarely require payment for
• Claims that the
trial is listed on ClinicalTrials.gov and is therefore NIH-approved. This may
not be true. The Web site is simply a listing; not all are legitimate trials.
• The bottom line:
Does the treatment sound too good to be true? If so, it probably is. Look for
concrete evidence that the treatment works and is safe.
Hundreds of clinics offer costly, unapproved and unproven stem cell
interventions, and patients may suffer physical and financial harm as a result.A Multi-Pronged Approach to Deal with
The International Society for Stem Cell Research (ISSCR)has
long been concerned that bad actors have co-opted the hope and promise of stem
cell science to prey on unsuspecting patients and their families.
We read with sadness and disappointment the many stories of people trying unproven therapies and being harmed, including going blind from injections into the eyes or suffering from a spinal tumor after an injection of stem cells.Patients left financially strapped, with no physical improvement in their condition and no way to reclaim their losses, are an underreported and underappreciated aspect of these treatments.
Since late 2017, the Food and Drug Administration has stepped up its
regulatory enforcement of stem cell therapies and provided a framework
for regenerative medicine products that provides guidelines for work in
this space.The agency has alerted many clinics and centers
that they are not in compliance and has pledged to bring additional enforcement
action if needed.
A Multi-Pronged Approach to Deal with Bad Actors The International Society for Stem Cell Research (ISSCR) has long been concerned that bad actors have co-opted the hope and promise of stem cell science to prey on unsuspecting patients and their families.
We read with sadness and disappointment the many stories of people trying
unproven therapies and being harmed, including going
blind from injections into the eyesor suffering from a spinal
tumor after an injection of stem cells.Patients left
financially strapped, with no physical improvement in their condition and no
way to reclaim their losses, are an underreported and underappreciated aspect
of these treatments.
Since late 2017, the Food and Drug Administration has stepped up its
regulatory enforcement of stem cell therapies and provided a framework
for regenerative medicine products that provides guidelines for work in
this space.The agency has alerted many clinics and centers
that they are not in compliance and has pledged to bring additional enforcement
action if needed.
In recent weeks, a federal judge granted the FDA a permanent injunction
against U.S. Stem Cell, Inc. and U.S. Stem Cell Clinic, LLC for adulterating
and misbranding its cellular products and operating outside of regulatory
authority.We hope this will send a strong message to other
clinics misleading patients with unapproved and potentially harmful cell-based
The Federal Trade Commission has also helped by identifying and curtailing
unsubstantiated medical claims in advertising by several clinics. Late in 2018
the FTC won a $3.3-million judgment against two California-based clinics for
deceptive health claims.
The Federal Trade Commission has also
helped by identifying and curtailing unsubstantiated medical claims in
advertising by several clinics. Late in 2018 the FTC won a $3.3-million
judgment against two California-based clinics for deceptive health claims.
These and other actions are needed to stem the tide of clinics offering
unproved therapies and the people who manage and operate them.
Improving Public Awareness
We’re hopeful that the FDA will help improve public awareness of these
issues and curb the abuses on ClinicalTrials.gov,a government-run Web site being misused by rogue clinics looking to
legitimize their treatments. They list pay-to-participate clinical trials on
the site, often without developing, registering or administering a real
The ISSCR Web site A Closer
Look at Stem Cellsincludes patient-focused information
about stem cells,with information written and vetted by stem
cell scientists.The site includes how and where to report
adverse events and false marketing claims by stem cell clinics.I
encourage you to visit and learn about what is known and unknown about stem
cells and their potential for biomedicine.The views expressed are those of the
author(s) and are not necessarily those of Scientific American.
The invention of GPS navigation systems has made finding your way around so much easier, providing simple instructions on how to get from point A to point B. Now, a new study shows that our bodies have their own internal navigation system that helps stem cells know where to go, and when, in order to build a human heart. And the study also shows what can go wrong when even a few cells fail to follow directions.
In this CIRM-supported study, a team of researchers at the Gladstone Institutes in San Francisco, used a new technique called single cell RNA sequencing to study what happens in a developing heart. Single cell RNA sequencing basically takes a snapshot photo of all the gene activity in a single cell at one precise moment. Using this the researchers were able to follow the activity of tens of thousands of cells as a human heart was being formed.
“This sequencing technique allowed us
to see all the different types of cells present at various stages of heart development
and helped us identify which genes are activated and suppressed along the way. We
were not only able to uncover the existence of unknown cell types, but we also
gained a better understanding of the function and behavior of individual
cells—information we could never access before.”
Then they partnered with a team at Luxembourg Centre for Systems
Biomedicine (LCSB) of the University of Luxembourg which ran a
computational analysis to identify which genes were involved in creating
different cell types. This highlighted one specific gene, called Hand2, that controls
the activity of thousands of other genes. They found that a lack of Hand2 in
mice led to an inability to form one of the heart’s chambers, which in turn led
to impaired blood flow to the lungs. The embryo was creating the cells needed
to form the chamber, but not a critical pathway that would allow those cells to
get where they were needed when they were needed.
Gifford says this has given us a deeper insight into how
cells are formed, knowledge we didn’t have before.
“Single-cell technologies can inform us about how organs
form in ways we couldn’t understand before and can provide the underlying cause
of disease associated with genetic variations. We revealed subtle differences
in very, very small subsets of cells that actually have catastrophic
consequences and could easily have been overlooked in the past. This is the
first step toward devising new therapies.”
These therapies are needed to help treat congenital heart
defects, which are the most common and deadly birth defects. There are more
than 2.5 million Americans with these defects. Deepak Srivastava, President of
Gladstone and the leader of the study, said the knowledge gained in this study
could help developed strategies to help address that.
to see the long-term consequences in adults, and right now, we don’t really
have any way to treat them. My hope is that if we can understand the genetic
causes and the cell types affected, we could potentially intervene soon after
birth to prevent the worsening of their state over time.
Modern medicine often involves the development of a drug or treatment outside the body, which is then given to a patient to fix, improve or even prevent their condition. But what if you could regenerate or heal the body using the cells and tissue already inside a patient?
Scientists at the Gladstone Institutes are pursuing such a strategy for heart disease. In a CIRM-funded study published today in the journal Cell, the team identified four genes that can stimulate adult heart muscle cells, called cardiomyocytes, to divide and proliferate within the hearts of living mice. This discovery could be further developed as a strategy to repair cardiac tissue damage caused by heart disease and heart attacks.
Regenerating the Heart
Heart disease is the leading cause of death in the US and affects over 24 million people around the world. When patients experience a heart attack, blood flow is restricted to the heart, and parts of the heart muscle are damaged or die due to the lack of oxygen. The heart is unable to regenerate new healthy heart muscle, and instead, cardiac fibroblasts generate fibrous scar tissue to heal the injury. This scar tissue impairs the heart’s ability to pump blood, causing it to work harder and putting patients at risk for future heart failure.
Deepak Srivastava, President of the Gladstone Institutes and a senior investigator there, has dedicated his life’s research to finding new ways to regenerate heart tissue. Previously, his team developed methods to reprogram mouse and human cardiac fibroblasts into beating cardiomyocytes in hopes of one day restoring heart function in patients. The team is advancing this research with the help of a CIRM Discovery Stage research grant, which will aid them in developing a gene therapy product that delivers reprogramming factors into scar tissue cells to regenerate new heart muscle.
In this new study, Srivastava took a slightly different approach and attempted to coax cardiomyocytes, rather than cardiac fibroblasts, to divide and regenerate the heart. During development, fetal cardiomyocytes rapidly divide to create heart tissue. This regenerative ability is lost in adult cardiomyocytes, which are unable to divide because they’ve already exited the cell cycle (a series of phases that a cell goes through that ultimately results in its division).
Deepak Srivastava (left) and first author Tamer Mohamed (right). Photo credits: Diana Rothery.
Unlocking proliferative potential
Srivastava had a hunch that genes specifically involved in the cell division could be used to jump-start an adult cardiomyocyte’s re-entry into the cell cycle. After some research, they identified four genes (referred to as 4F) involved in controlling cell division. When these genes were turned on in adult cardiomyocytes, the cells started to divide and create new heart tissue.
This 4F strategy worked in mouse and rat cardiomyocytes and also was successful in stimulating cell division in 15%-20% of human cardiomyocytes. When they injected 4F into the hearts of mice that had suffered heart attacks, they observed an improvement in their heart function after three months and a reduction in the size of the scar tissue compared to mice that did not receive the injection.
The team was able to further refine their method by replacing two of the four genes with chemical inhibitors that had similar functions. Throughout the process, the team did not observe the development of heart tumors caused by the 4F treatment. They attributed this fact to the short-term expression of 4F in the cardiomyocytes. However, Srivastava expressed caution towards using this method in a Gladstone news release:
“In human organs, the delivery of genes would have to be controlled carefully, since excessive or unwanted cell division could cause tumors.”
First stop heart, next stop …
This study suggests that it’s possible to regenerate our tissues and organs from within by triggering adult cells to re-enter the cell cycle. While more research is needed to ensure this method is safe and worthy of clinical development, it could lead to a regenerative treatment strategy for heart failure.
Srivastava will continue to unravel the secrets to the proliferative potential of cardiomyocytes but predicts that other labs will pursue similar methods to test the regenerative potential of adult cells in other tissues and organs.
“Heart cells were particularly challenging because when they exit the cell cycle after birth, their state is really locked down—which might explain why we don’t get heart tumors. Now that we know our method is successful with this difficult cell type, we think it could be used to unlock other cells’ potential to divide, including nerve cells, pancreatic cells, hair cells in the ear, and retinal cells.”
New law targets stem cell clinics that offer therapies not approved by the FDA
For some time now CIRM and others around California have been warning consumers about the risks involved in going to clinics that offer stem cell therapies that have not been tested in a clinical trial or approved by the U.S. Food and Drug Administration (FDA) for use in patients.
Now a new California law, authored by State Senator Ed Hernandez (D-West Covina) attempts to address that issue. It will require medical clinics whose stem cell treatments are not FDA approved, to post notices and provide handouts to patients warning them about the potential risk.
In a news release Sen. Hernandez said he hopes the new law, SB 512, will protect consumers from early-stage, unproven experimental therapies:
“There are currently over 100 medical offices in California providing non-FDA approved stem cell treatments. Patients spend thousands of dollars on these treatments, but are totally unaware of potential risks and dangerous side effects.”
Sen. Hernandez’s staffer Bao-Ngoc Nguyen crafted the bill, with help from CIRM Board Vice Chair Sen. Art Torres, Geoff Lomax and UC Davis researcher Paul Knoepfler, to ensure it targeted only clinics offering non-FDA approved therapies and not those offering FDA-sanctioned clinical trials.
For example the bill would not affect CIRM’s Alpha Stem Cell Clinic Network because all the therapies offered there have been given the green light by the FDA to work with patients.
Using your own skin as a blood glucose monitor
One of the many things that people with diabetes hate is the constant need to monitor their blood sugar level. Usually that involves a finger prick to get a drop of blood. It’s simple but not much fun. Attempts to develop non-invasive monitors have been tried but with limited success.
Now researchers at the University of Chicago have come up with another alternative, using the person’s own skin to measure their blood glucose level.
Xiaoyang Wu and his team accomplished this feat in mice by first creating new skin from stem cells. Then, using the gene-editing tool CRISPR, they added in a protein that sticks to sugar molecules and another protein that acts as a fluorescent marker. The hope was that the when the protein sticks to sugar in the blood it would change shape and emit fluorescence which could indicate if blood glucose levels were too high, too low, or just right.
The team then grafted the skin cells back onto the mouse. When those mice were left hungry for a while then given a big dose of sugar, the skin “sensors” reacted within 30 seconds.
The researchers say they are now exploring ways that their findings, published on the website bioRxiv, could be duplicated in people.
While they are doing that, we are supporting ViaCytes attempt to develop a device that doesn’t just monitor blood sugar levels but also delivers insulin when needed. You can read about our recent award to ViaCyte here.
Dr. Deepak Srivastava
Stem Cell Champion, CIRM grantee, and all-round-nice guy named President of Gladstone Institutes
I don’t think it would shock anyone to know that there are a few prima donnas in the world of stem cell research. Happily, Dr. Deepak Srivastava is not one of them, which makes it such a delight to hear that he has been appointed as the next President of the Gladstone Institutes in San Francisco.
Deepak is a gifted scientist – which is why we have funded his work – a terrific communicator and a really lovely fella; straight forward and down to earth.
In a news release announcing his appointment – his term starts January 1 next year – Deepak said he is honored to succeed the current President, Sandy Williams:
“I joined Gladstone in 2005 because of its unique ability to leverage diverse basic science approaches through teams of scientists focused on achieving scientific breakthroughs for mankind’s most devastating diseases. I look forward to continue shaping this innovative approach to overcome human disease.”
Describing the work of a government agency is not the most exciting of topics. Books on the subject would probably be found in the “Self-help for Insomniacs” section of a good bookstore (there are still some around). But at CIRM we are fortunate. When we talk about what we do, we don’t talk about the mechanics of our work, we talk about our mission: accelerating stem cell therapies to people with unmet medical needs.
Yesterday at the Gladstone Institutes in San Francisco we did just that, talking about the progress being made in stem cell research to an audience of friends, supporters and patient advocates. We had a lot to talk about, including the 35 clinical trials we have funded so far, and our goals and hopes for the future.
We were lucky to have Dr. Deepak Srivastava and Dr. Steve Finkbeiner from Gladstone join us to talk about their work. Some people are good scientists, some are good communicators. Deepak and Steve are great scientists and equally great communicators.
Deepak Srivastava highlighted ongoing stem cell research at the Gladstone (Photo: Todd Dubnicoff/CIRM)
Deepak is the Director of the Roddenberry Stem Cell Center at Gladstone (and yes, it’s named after Gene Roddenberry of Star Trek fame) and an expert on heart disease. He talked about how advances in research have enabled us to turn heart scar tissue cells into new heart muscle cells, creating the potential to use a person’s own cells to help them recover from a heart attack.
“If you have a heart attack, your heart turns that muscle into scar tissue which affects the heart’s ability to pump blood around the body. We identified a combination of factors that support cells that are already in your heart and we have found a way of converting those scar cells into muscle. This could help repair the heart enough so you may not need a transplant, but you can lead a much more normal life.”
He said this research is now advancing to the point where they hope it could be ready for testing in people in the not too distant future and joked that his father, who has had a heart attack, volunteered to be the second person to try it. “Not the first but definitely the second.”
Steve, who is the Director of the Taube/Koret Center for Neurodegenerative Disease Research, specializes in problems in the brain; everything from Alzheimer’s and Parkinson’s to schizophrenia and ALS (also known as Lou Gehrig’s disease.
He talked about his uncle, who has end stage Parkinson’s disease, and how he sees first-hand how devastating this neurodegenerative disease is, and how that personal connection helps motivate him to work ever harder.
He talked about how so many therapies that look promising in mice fail when they are tested in people:
“A huge motivation for me has been to try and figure out a more reliable way to test these potential therapies and to move discoveries from the lab and into clinical trials in patients.”
Steve is using ordinary skin cells or tissue samples, taken from people with Parkinson’s and Alzheimer’s and other neurological conditions, and using the iPSC technique developed by Shinya Yamanaka (who is a researcher at Gladstone and also Director of CIRA in Japan) turns them into the kinds of cells found in the brain. These cells then enable him to study how these different diseases affect the brain, and come up with ways that might stop their progress.
Steve Finkbeiner is using human stem cells to model brain diseases (Photo: Todd Dubnicoff/CIRM)
He uses a robotic microscope – developed at Gladstone – that allows his team to study these cells and test different potential therapies 24 hours a day, seven days a week. This round-the-clock approach will hopefully help speed up his ability to find something that help patients.
The CIRM speakers – Dr. Maria Millan, our interim President and CEO – and Sen. Art Torres (ret.) the Vice Chair of our Board and a patient advocate for colorectal cancer – talked about the progress we are making in helping push stem cell research forward.
Dr. Millan focused on our clinical trial work and how our goal is to create a pipeline of promising projects from the work being done by researchers like Deepak and Steve, and move those out of the lab and into clinical trials in people as quickly as possible.
Sen. Art Torres (Ret.) (Photo: Todd Dubnicoff/CIRM)
Sen. Torres focused on the role of the patient advocate at CIRM and how they help shape and influence everything we do, from the Board’s deciding what projects to support and fund, to our creating Clinical Advisory Panels which involve a patient advocate helping guide clinical trial teams.
The event is one of a series that we hold around the state every year, reporting back to our friends and supporters on the progress being made. We feel, as a state agency, that we owe it to the people of California to let them know how their money is being spent.
Patients and Patient Advocates are at the heart of everything we do at CIRM. That’s why we are holding three free public events in the next few months focused on updating you on the stem cell research we are funding, and our plans for the future.
Right now we have 33 projects that we have funded in clinical trials. Those range from heart disease and stroke, to cancer, diabetes, ALS (Lou Gehrig’s disease), two different forms of vision loss, spinal cord injury and HIV/AIDS. We have also helped cure dozens of children battling deadly immune disorders. But as far as we are concerned we are only just getting started.
Over the course of the next few years, we have a goal of adding dozens more clinical trials to that list, and creating a pipeline of promising therapies for a wide range of diseases and disorders.
That’s why we are holding these free public events – something we try and do every year. We want to let you know what we are doing, what we are funding, how that research is progressing, and to get your thoughts on how we can improve, what else we can do to help meet the needs of the Patient Advocate community. Your voice is important in helping shape everything we do.
The first event is at the Gladstone Institutes in San Francisco on Wednesday, September 6th from noon till 1pm. The doors open at 11am for registration and a light lunch.
Here’s a link to an Eventbrite page that has all the information about the event, including how you can RSVP to let us know you are coming.
We are fortunate to be joined by two great scientists, and speakers – as well as being CIRM grantees- from the Gladstone Institutes, Dr. Deepak Srivastava and Dr. Steve Finkbeiner.
Dr. Srivastava is working on regenerating heart muscle after it has been damaged. This research could not only help people recover from a heart attack, but the same principles might also enable us to regenerate other organs damaged by disease. Dr. Finkbeiner is a pioneer in diseases of the brain and has done ground breaking work in both Alzheimer’s and Huntington’s disease.
We have two other free public events coming up in October. The first is at UC Davis in Sacramento on October 10th (noon till 1pm) and the second at Cedars-Sinai in Los Angeles on October 30th (noon till 1pm). We will have more details on these events in the coming weeks.
We look forward to seeing you at one of these events and please feel free to share this information with anyone you think might be interested in attending.
Aging is inevitable no matter how much you exercise, sleep or eat healthy. There is no magic pill or supplement that can thwart growing older. However, preventing certain age-related diseases is a different story. Genetic mutations can raise the risk of acquiring age-related diseases like heart disease, diabetes, cancer and dementia. And scientists are on the hunt for treatments that target these mutations in hopes of preventing these diseases from happening.
Telomeres shown in white act as protective caps at the ends of chromosomes.
Another genetic component that can accelerate diseases of aging are telomeres. These are caps made up of repeat sequences of DNA that sit at the ends of chromosomes and prevent the loss of important genetic material housed within chromosomes. Healthy cells have long telomeres, and ascells divide these telomeres begin to shorten. If telomere shortening is left unchecked, cells become unhealthy and either stop growing or self-destruct.
Cells have machinery to regrow their telomeres, but in most cases, the machinery isn’t activated and over time, the resulting shortened telomeres can lead to problems like an impaired immune system and organ degeneration. Shortened telomeres are associated with age-related diseases, but the reasons why have remained elusive until recently.
Scientists from the Gladstone Institutes have found a clue to this telomere puzzle that they shared in a study published yesterday in the Journal of Clinical Investigation. This research was funded in part by a CIRM Discovery stage award.
In their study, the team found that mice with a mutation that causes a heart condition known as calcific aortic valve disease (CAVD) were more likely to get the disease if they had short telomeres. CAVD causes the heart valves and vessels to turn hard as rock due to a buildup of calcium. It’s the third leading cause of heart disease and the only effective treatment requires surgery to replace the calcified parts of the heart.
Old age and mutations in one of the copies of the NOTCH1 gene can cause CAVD in humans. However, attempts to model CAVD in mice using the same NOTCH1 mutation have failed to produce symptoms of the disease. The team at Gladstone knew that mice inherently have longer telomeres than humans and hypothesized that these longer telomeres could protect mice with the NOTCH1 mutation from getting CAVD.
They decided to study NOTCH1 mutant mice that had short telomeres and found that these mice had symptoms of CAVD including hardened arteries. Furthermore, mice that had the shortest telomeres had the most severe heart-related symptoms.
First author on the study Christina Theodoris, explained in a Gladstone news release how telomere length matters in animal models of age-related diseases:
“Our findings reveal a critical role for telomere length in a mouse model of age-dependent human disease. This model provides a unique opportunity to dissect the mechanisms by which telomeres affect age-dependent disease and also a system to test novel therapeutics for aortic valve disease.”
Deepak Srivastava and Christina Theodoris created mouse models of CAVD that may be used to test drug therapies for the disease. (Photo: Chris Goodfellow, Gladstone Institutes)
The team believes that there is a direct relationship between short telomeres and CAVD, likely through alterations in the activity of gene networks related to CAVD. They also propose that telomere length could influence how severe the symptoms of this disease manifest in humans.
This study is important to the field because it offers a new strategy to study age-related diseases in animal models. Senior author on the study, Dr. Deepak Srivastava, elaborated on this concept:
Deepak Srivastava, Gladstone Institutes
“Historically, we have had trouble modeling human diseases caused by mutation of just one copy of a gene in mice, which impedes research on complex conditions and limits our discovery of therapeutics. Progressive shortening of longer telomeres that are protective in mice not only reproduced the clinical disease caused by NOTCH1 mutation, it also recapitulated the spectrum of disease severity we see in humans.”
Going forward, the Gladstone team will use their new mouse model of CAVD to test drug candidates that have the potential to treat CAVD in humans. If you want to learn more about this study, watch this Gladstone video featuring an interview of Dr. Srivastava about this publication.
Although heart muscle cells, or cardiomyocytes, are specialized to help pump blood to the organs, they nonetheless carry all the genetic instructions for becoming a nerve cell, an intestinal cell, a liver or any cell type in the body. But at the moment in time that the fetal heart begins to develop, master switch proteins, called transcription factors, act like the first tile in an extremely complex pattern of dominos and set off a chain of events which lead to the activation of heart muscle specific genes in cardiomyocytes as well as the silencing of genes important for the development other cells types.
It’s truly amazing that this process comes together to create functioning hearts in the about 355,000 babies that are born in the world each day. But it isn’t always flawless as heart defects occur in about 1% of all live births. By studying a family with a history of heart defects, scientists at the Gladstone Institutes have gained a deeper understanding of how gene networks go awry, causing heart defects as well as heart disease later in life. This CIRM-funded work was published today in Cell.
Half the children in the family studied by the Gladstone team were born with a hole in the wall between the two chambers of the heart. Back in 2003, the family approached Deepak Srivastava, head of the cardiovascular institute at Gladstone, for help. A genetic analysis by Srivastava’s team found that all of the affected children carried a mutation in the GATA4 gene, which encodes a heart specific transcription factor protein. Seven years later the children developed heart disease that led to weaker heart pumping. Although the two heart problems were not related, they suspected both were caused by the GATA4 mutation and sought to understand how that could be the case.
Srivastava’s team sought to understand how the GATA4 mutation could be causing both health problems. They collected skin samples from the affected children and generated cardiomyocytes using the induced pluripotent stem cell technique. Cells were also collected from the children’s healthy siblings. In the laboratory, the cells were analyzed for how well they functioned, such as their ability to contract. All of these tests showed that the cells carrying the GATA4 mutation had impaired function compared to the healthy cells. These findings provide a basis for the heart disease found in the children during their teens.
In terms of the heart wall defect, the team examined the GATA4 protein’s interaction with the protein TBX5, another transcription factor that is also mutated in cases of this defect. Both proteins regulate genes by directly binding to DNA as well as interacting with each other. In cells with the defective GATA4, the research discovered TBX5 did not bind well to the DNA. The lack of TBX5 led to a disruption in the activation of genes that play a role in the development of the heart wall.
TBX5 and GATA4 also work together in cardiomyocytes to silence genes that play a role in other cell types. But the scientists found that the because the GATA4 mutation hindered its interaction with TBX5, those non-heart specific genes we’re no longer repressed causing further disruption to proper cardiomyocyte development. Srivastava summed up these results in an institute press release:
“By studying the patients’ heart cells in a dish, we were able to figure out why their hearts were not pumping properly. Investigating their genetic mutation revealed a whole network of genes that went awry, first causing septal [heart wall] defects and then the heart muscle dysfunction.”
Now, because GATA4 and TBX5 are those first domino tiles in very intricate networks of genes, targeting those proteins for future therapy development wouldn’t be wise. Their effects are so widespread that blocking their actions would do more harm than good. But finding drugs that might affect only a branch of GATA4/TBX5 actions could result in new therapy approaches to heart defects and disease.
Deepak Srivastava and Yen-Sin Ang [Photo: Chris Goodfellow, Gladstone Institutes]
Yen-Sin Ang, the first author on the report, thinks these finding could prove fruitful for other diseases as well:
“It’s amazing that by studying genes in a two-dimensional cluster of heart cells, we were able to discover insights into a disease that affects a complicated three-dimensional organ. We think this conceptual framework could be used to study other diseases caused by mutations in proteins that serve as master regulators of whole gene networks.”
A stem cell champion was crowned last month. Dr. Takahashi from the RIKEN center in Japan received the prestigious Ogawa-Yamanaka Prize for developing a human iPS cell therapy to treat a debilitating eye disease called macular degeneration. We wrote about the event held at the Gladstone Institutes in a previous blog and saved the juicy insights from Dr. Takahashi’s scientific presentation and her CIRM-exclusive interview for today. We also put together a two minute video (see below) based on the interview with her as well as with Dr. Deepak Srivastava, Director of the Gladstone Institute of Cardiovascular Disease and Mr. Hiro Ogawa, a co-founder of the Ogawa-Yamanaka Prize.
Dawn of iPS Cells
As part of the ceremony, Dr. Takahashi gave a scientific talk on the “new world that iPS cells will bring”. She began with a historical overview of stem cell research, starting with embryonic stem cells and the immune rejection and ethical issues associated with their use. She then discussed Dr. Yamanaka’s game-changing discovery of iPS cells, which offered new strategies for disease modeling and potential treatments that avoid some of the issues can complicate embryonic stem cells.
Her excitement over this discovery was palpable as she explained how she immediately jumped into the iPS cell field and got her hands dirty. Knowing that this technology could have huge implications for regenerative medicine and the development of stem cell therapies, she made herself a seemingly unattainable promise. “I said to myself, I will apply iPS cells to humans within five years. And I became a woman of her words.”
An iPS cell world
Dr. Takahashi went on to tell her success story, and why she chose to develop an iPS cell therapy to treat a disease of blindess, age-related macular degeneration (AMD). She explained how AMD is a serious unmet medical need. The current treatment involves injections of an antibody that blocks the activity of a growth factor called VEGF. This factor causes an overgrowth of blood vessels in the eye, which does major damage to the cells in the retina and can cause blindness. This therapy however, is only useful for some forms of AMD not all.
Dr. Masayo Takahashi describing her team’s iPS-based therapy for macular degeneration during the inaugural ceremony for the Ogawa-Yamanaka Prize at The Gladstone Institutes.
She believed she could fix this problem by developing an iPS cell technology that would replace lost cells in the eye in AMD patients. To a captivated crowd, she described how she was able to generate a sheet of human iPS derived cells called retinal pigment epithelial (RPE) cells from a patient with AMD. This sheet was transplanted into the eye of the patient in the first ever iPS cell clinical trial. The transplant was successful and the patient had no adverse effects to the treatment.
While the clinical trial is currently on hold, Dr. Takahashi explained that she and her team learned a lot from this experience. They are currently pursuing additional safety measures for their iPS cell technology to make sure that the stem cell transplants will not cause cancer or other bad outcomes in humans.
Autologous vs. Allogeneic?
Another main topic in her speech, was the choice between using autologous (iPS cells made from a patient and transplanted back into the same patient) and allogeneic (iPS cells made from a donor and then transplanted into a patient) iPS cells for transplantation in humans. Dr. Tahakashi’s opinion was that autologous would be ideal, but not scaleable due to high costs and the amount of time it would take to make iPS cell lines for individual patients.
iPS cells reprogrammed from a woman’s skin. Blue shows nuclei. Green and red indicate proteins found in reprogrammed cells but not in skin cells (credit: Kathrin Plath / UCLA).
Her solution is to use an arsenal of allogeneic iPS cells that can be transplanted into patients without rejection by the immune system. This may be possible if both the donor and the patient share the same combination (called a “haplotype”) of cell surface proteins on their immune cells called human leukocyte antigens (HLA). She highlighted the work ongoing in Japan to generate a stock of HLA haplotype matched iPS cell lines that could be used for most of the Japanese population.
Changing the regulatory landscape in Japan
It was clear from her talk that her prize winning accomplishments didn’t happen without a lot of blood, sweat, and tears both at the bench and in the regulatory arena. In a CIRM exclusive interview, Dr. Takahashi further explained how her pioneering efforts to bring iPS cells to patients helped revolutionize the regulatory landscape in Japan to make it faster and easier to test iPS cells in the clinic.
“The power of iPS cells changed the Japanese [regulatory] law dramatically. We made a new chapter for regenerative medicine in pharmaceutical law. With that law, the steps are very quick for cell therapy. In the new chapter [of the law] … conditional approval will be given if you prove the safety of the cell [therapy]. It’s very difficult to show the efficacy completely in a statistical manner for regenerative medicine. So the law says we don’t have to prove the efficacy [of the therapy] thoroughly with thousands of patients. Only a small number of patients are needed for the conditional approval. That’s the big difference.”
We were curious about Dr. Takahashi’s involvement in getting these regulatory changes to pass, and learned that she played a significant role on the academic side to convince the Japanese ministry to change the laws.
“This law was made in the cooperation with the ministry and academia. That was one thing that had never happened before. Academia means mainly the Japanese society for the regenerative medicine, and I’m a committee member of that. So we talked about the ideal law for regenerative medicine, and our society suggested various points to the ministry. And to our surprise, the ministry accepted almost all of the points and included them into the law. That was wonderful. Usually we are very conservative and slow in changing, but this time, I was amazed how quickly the law has been changed. It’s the power of iPS cells.”
The iPS cell future is now
As a champion stem cell scientist and a leader in regenerative medicine, Dr. Takahashi took the opportunity at the end of the event to emphasize that all scientists and clinicians in the iPS cell therapy field need to consider three things: develop safe protocols for generating iPS cells that become standard practice, understand the patient’s needs by focusing on how to benefit patients the most, and think of iPS cells as a treatment and consider the risk when developing these therapies.
The new world of iPS cells is opening doors onto uncharted territory, but Dr. Takahashi’s wise words provide a solid roadmap for the future success of iPS cell therapies.