How some brilliant research may have uncovered a potential therapy for Alzheimer’s 

Dr. Nicole Koutsodendris, photo courtesy Gladstone Institutes

In the world of scientific research, the people doing clinical trials tend to suck up all the oxygen in the room. They’re the stars, the ones who are bringing potential therapies to patients. However, there’s another group of researchers who toil away in the background, but who are equally deserving of praise and gratitude. 

Dr. Lana Zholudeva, photo courtesy Gladstone Institutes

These are the scientists who do basic or discovery-level research. This is where all great therapies start. This is where a researcher gets an idea and tests it to see if it holds promise. A good idea and a scientist who asks a simple question, “I wonder if…..”  

Dr. Yadong Huang, Photo courtesy Gladstone Institutes

In our latest “Talking ‘Bout (re)Generation” podcast we talk to three researchers who are asking those questions and getting some truly encouraging answers. They are scientists at the Gladstone Institutes in San Francisco: one seasoned scientist and two young post-docs trying to make a name for themselves. And they might just have discovered a therapy that could help people battling Alzheimer’s disease. 

Enjoy the podcast.


  

Newly-developed Organoid Mimics How Gut and Heart Tissues Arise Cooperatively From Stem Cells 

Microscopy image of the new type of organoid created by Todd McDevitt, Ana Silva, and their colleagues in which heart tissue (red, purple, and orange masses) and gut tissue (blue and green masses) are growing together. Captured by Ana Silva.
Microscopy image of the new type of organoid created by Todd McDevitt, Ana Silva, and their colleagues in which heart tissue (red, purple, and orange masses) and gut tissue (blue and green masses) are growing together. Captured by Ana Silva. Image courtesy of Gladstone Institutes.

Scientists at Gladstone Institutes have discovered how to grow a first-of-its-kind organoid—a three-dimensional, organ-like cluster of cells—that mimics how gut and heart tissues arise cooperatively from stem cells.  

The study was supported by a grant from CIRM and the Gladstone BioFulcrum Heart Failure Research Program. 

Gladstone Senior Investigator Todd McDevitt, PhD said this first-of-its-kind organoid could serve as a new tool for laboratory research and improve our understanding of how developing organs and tissues cooperate and instruct each other. 

McDevitt’s team creates heart organoids from human induced pluripotent stem cells, coaxing them into becoming heart cells by growing them in various cocktails of nutrients and other naturally occurring substances. In this case, the scientists tried a different cocktail to potentially allow a greater variety of heart cells to form. 

To their surprise, they found that the new cocktail led to organoids that contained not only heart, but also gut cells. 

“We were intrigued because organoids normally develop into a single type of tissue—for example, heart tissue only,” says Ana Silva, PhD, a postdoctoral scholar in the McDevitt Lab and first author of the new study. “Here, we had both heart and gut tissues growing together in a controlled manner, much as they would in a normal embryo.” 

Shown here is the study’s first author, Ana Silva, a postdoctoral scholar in the McDevitt Lab. Image courtesy of Gladstone Institutes.

The researchers also found that compared to conventional heart organoids, the new organoids resulted in much more complex and mature heart structures—including some resembling more mature-like blood vessels. 

These organoids offer a promising new look into the relationship between developing tissues, which has so far relied on growing single-tissue organoids separately and then attempting to combine them. Not only that, the organoids could help clarify how the process of human development can go wrong and provide insight on congenital disorders like chronic atrial and intestinal dysrhythmias that are known to affect both heart and gut development. 

“Once it became clear that the presence of the gut tissue contributed to the maturity of the heart tissue, we realized we had arrived at something new and special,” says McDevitt. 

Read the official release about this study on Gladstone’s website

The study findings are published in the journal Cell Stem Cell.

Creating a diverse group of future scientists

Students in CIRM’s Bridges program showing posters of their work

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:

AWARDINSTITUTIONTITLEAMOUNT
EDUC4-12751Cedars-SinaiCIRM Training Program in Translational Regenerative Medicine    $4,999,333
EDUC4-12752UC RiversideTRANSCEND – Training Program to Advance Interdisciplinary Stem Cell Research, Education, and Workforce Diversity    $4,993,115
EDUC4-12753UC Los AngelesUCLA Training Program in Stem Cell Biology    $5 million
EDUC4-12756University of Southern CaliforniaTraining Program Bridging Stem Cell Research with Clinical Applications in Regenerative Medicine    $5 million
EDUC4-12759UC Santa CruzCIRM Training Program in Systems Biology of Stem Cells    $4,913,271
EDUC4-12766Gladstone Inst.CIRM Regenerative Medicine Research Training Program    $5 million
EDUC4-12772City of HopeResearch Training Program in Stem Cell Biology and Regenerative Medicine    $4,860,989
EDUC4-12782StanfordCIRM Scholar Training Program    $4,974,073
EDUC4-12790UC BerkeleyTraining the Next Generation of Biologists and Engineers for Regenerative Medicine    $4,954,238
EDUC4-12792UC DavisCIRM Cell and Gene Therapy Training Program 2.0    $4,966,300
EDUC4-12802Children’s Hospital of Los AngelesCIRM Training Program for Stem Cell and Regenerative Medicine Research    $4,999,500
EDUC4-12804UC San DiegoInterdisciplinary Stem Cell Training Grant at UCSD III    $4,992,446
EDUC4-12811ScrippsTraining Scholars in Regenerative Medicine and Stem Cell Research    $4,931,353
EDUC4-12812UC San FranciscoScholars Research Training Program in Regenerative Medicine, Gene Therapy, and Stem Cell Research    $5 million
EDUC4-12813Sanford BurnhamA Multidisciplinary Stem Cell Training Program at Sanford Burnham Prebys Institute, A Critical Component of the La Jolla Mesa Educational Network    $4,915,671  
EDUC4-12821UC Santa BarbaraCIRM Training Program in Stem Cell Biology and Engineering    $1,924,497
EDUC4-12822UC IrvineCIRM Scholars Comprehensive Research Training Program  $5 million
EDUC4-12837Lundquist Institute for Biomedical InnovationStem Cell Training Program at the Lundquist Institute    $4,999,999

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.

Heads or tails? Stem cells help guide the decision

Two cell embryo

There are many unknown elements for what triggers the cells in an embryo to start dividing and multiplying and becoming every single cell in the body. Now researchers at the Gladstone Institutes in San Francisco have uncovered one of those elements, how embryos determine which cells become the head and which the tail.

In this CIRM-funded study the Gladstone team, led by Dr. Todd McDevitt, discovered almost by chance how the cells align in a heads-to-tail arrangement.

Todd McDevitt

They had created an organoid made from brain cells when they noticed that some of the cells were beginning to gather in an elongated fashion, in the same way that spinal cords do in a developing fetus.

In a news article, Nick Elder, a graduate student at Gladstone and the co-author of the study, published in the journal Development, says this was not what they had anticipated would happen: “Organoids don’t typically have head-tail directionality, and we didn’t originally set out to create an elongating organoid, so the fact that we saw this at all was very surprising.”

Further study enabled the team to identify which molecules were involved in signaling specific genes to switch on and off. These were similar to the process previously identified in developing mouse embryos.

“This is such a critical point in the early development of any organism, so having a new model to observe it and study it in the lab is very exciting,” says McDevitt.

This is not just of academic interest either, it could have real world implications in helping understand what causes miscarriages or birth defects.

“We can use this organoid to get at unresolved human developmental questions in a way that doesn’t involve human embryos,” says Dr. Ashley Libby, another member of the team. “For instance, you could add chemicals or toxins that a pregnant woman might be exposed to, and see how they affect the development of the spinal cord.”

How stem cells play “follow the leader”

Todd McDevitt, PhD., Photo: courtesy Gladstone Institutes

It’s hard enough trying to follow the movements of individuals in a crowd of people but imagine how much harder it is to follow the movements of stem cells, crowded into a tiny petri dish. Well, researchers at the Gladstone Institutes in San Francisco have done just that.

In a CIRM-funded study ($5.85M) Dr. Todd McDevitt and his team created a super smart artificial intelligence way of tracking the movements of hundreds of stem cells growing together in a colony, and even identify “leaders” in the pack.

In our bodies groups of stem cells are able to move in specific ways to form different organs and tissues when exposed to the right environment. Unfortunately, we are still trying to learn what “the right environment” is for different organs.

In a news release, McDevitt, the senior author of the paper published in the journal Stem Cell Reports, says this method of observing cells may help us better understand that.

“If I wanted to make a new human heart right now, I know what types of cells are needed, and I know how to grow them independently in dishes. But we really don’t know how to get those cells to come together to form something as complex as a heart. To accomplish that, we need more insights into how cells work cooperatively to arrange themselves.”

Normally scientists watch cells by tagging them with a fluorescent marker so they can see them under a microscope. But this is slow, painstaking work and not particularly accurate. This new method used a series of what are called “neural networks”, which are artificial intelligence (AI) programs that can detect patterns in the movements of the cells. When combined together the networks proved to be able to track the movement of 95 percent of the cells. Humans by comparison can only manage up to 90 percent. But the nets were not only sharper, they were also faster, much faster, some 500 times faster.

This enhanced ability to watch the cells showed that instead of being static most of the time, as had previously been thought, they were actually on the move a lot of the time. They would move around for 15 minutes and then take a breather for ten minutes (time for the stem cell equivalent of a cup of tea perhaps).  

Some cells moved around a lot in one direction, while others just seemed to shuffle around in the same area. Some cells even seemed to act as “leaders” while other cells appeared to be “followers” and shuffle along behind them.

None of this would have been visible without the power of the AI networks and McDevitt says being able to tap into this could help researchers better understand how to use these complex movements.

“This technique gives us a much more comprehensive view of how cells behave, how they work cooperatively, and how they come together in physical space to form complex organs.

Follow the Leader is not just a kids’ game anymore. Now it’s a scientific undertaking.

New technique maps out diversity and location of cells in tissue or tumor

Image Description: Alex Marson is part of a team of researchers who developed a new technique to map the specialized diversity and spatial location of individual cells within a tissue or tumor. Photo Credit: Anastasiia Sapon

All the cells in your body work together and each can have a different role. Their individual function not only depends on cell type, but can also depend on their specific location and surroundings.

A CIRM supported and collaborative study at the Gladstone Institutes, UC San Francisco (UCSF), and UC Berkeley has developed a more efficient method than ever before to simultaneously map the specialized diversity and spatial location of individual cells within a tissue or a tumor.

The technique is named XYZeq and involves segmenting a tissue into microscopic regions. Within each of these microscopic grids, each cell’s genetic information is analyzed in order to better understand how each particular cell functions relative to its spacial location.

For this study, the team obtained tissue from mice with liver and spleen tumors. A slice of tissue was then placed on a slide that divides the tissue into hundreds of “microwells” the size of a grain of salt. Each cell in the tissue gets tagged with a unique “molecular barcode” that represents the microwell it’s contained in, much like a zip code. The cells are then mixed up and assigned a second barcode to ensure that each cell within a given square can be individually identified, similar to a street address within a zip code. Finally, the genetic information in the form of RNA from each cell is analyzed. Once the results are obtained, both barcodes tell the researchers exactly where in the tissue it came from.

The team found that some cell types located near the liver tumor were not evenly spaced out. They also found immune cells and specific types of stem cells clustered in certain regions of the tumor. Additionally, certain stem cells had different levels of some RNA molecules depending on how far they resided from the tumor.

The researchers aren’t entirely sure what this pattern means, but they believe that it’s possible that signals generated by or near the tumor affect what nearby cells do.

In a press release, Alex Marson, M.D., Ph.D., a senior author of the study, elaborates on what the XYZeq technology could mean for disease modeling.

“I think we’re actually taking a step toward this being the way tissues are analyzed to diagnose, characterize, or study disease; this is the pathology of the future.”

The full results of the study were published in Science Advances.

Persistence pays off in search for clue to heart defects

A team of scientists led by Benoit Bruneau (left), including Irfan Kathiriya (center) and Kavitha Rao (right), make inroads into understanding what genes are improperly deployed in some cases of congenital heart disease.  Photo courtesy Gladstone Institute

For more than 20 years Dr. Benoit Bruneau has been trying to identify the causes of congenital heart disease, the most common form of birth defect in the U.S. It turns out that it’s not one cause, but many.

Congenital heart disease covers a broad range of defects, some relatively minor and others life-threatening and even fatal. It’s been known that a mutation in a gene called TBX5 is responsible for some of these defects, so, in a CIRM-funded study ($1.56 million), Bruneau zeroed in on this mutation to see if it could help provide some answers.

In the past Bruneau, the director of the Gladstone Institute of Cardiovascular Disease, had worked with a mouse model of TBX5, but this time he used human induced pluripotent stem cells (iPSCs). These are cells that can be manipulated in the lab to become any kind of cell in the human body. In a news release Bruneau says this was an important step forward.

“This is really the first time we’ve been able to study this genetic mutation in a human context. The mouse heart is a good proxy for the human heart, but it’s not exactly the same, so it’s important to be able to carry out these experiments in human cells.”

The team took some iPSCs, changed them into heart cells, and used a gene editing tool called CRISPR-Cas9 to create the kinds of mutations in TBX5 that are seen in people with congenital heart disease. What they found was some genes were affected a lot, some not so much. Which is what you might expect in a condition that causes so many different forms of problems.

“It makes sense that some are more affected than others, but this is the first experimental data in human cells to show that diversity,” says Bruneau.

But they didn’t stop there. Oh no. Then they did a deep dive analysis to understand how the different ways that different cells were impacted related to each other. They found some cells were directly affected by the TBX5 mutation but others were indirectly affected.

The study doesn’t point to a simple way of treating congenital heart disease but Bruneau says it does give us a much better understanding of what’s going wrong, and perhaps will give us better ideas on how to stop that.

“Our new data reveal that the genes are really all part of one network—complex but singular—which needs to stay balanced during heart development. That means if we can figure out a balancing factor that keeps this network functioning, we might be able to help prevent congenital heart defects.”

The study is published in the journal Developmental Cell.

CIRM-funded study discovers potential therapy for one of the leading causes of heart disease

Dr. Deepak Srivastava and his team found a drug candidate that could help prevent tens of thousands of heart surgeries every year. Image Credit: Gladstones Institute

According to the Center for Disease Control and Prevention (CDC), heart disease is the leading cause of death for men, women, and people of most racial and ethnic groups in the United States. About 655,000 Americans die from heart disease each year, which is about one in every four deaths.

Calcific aortic valve disease, the third leading cause of heart disease overall, occurs when calcium starts to accumulate in the heart valves and vessels over time, causing them to gradually harden like bone. This leads to obstruction of blood flow out of the heart’s pumping chamber, causing heart failure. Unfortunately there is no treatment for this condition, leaving patients only with the option of surgery to replace the heart valve once the hardening is severe enough.

But thanks to a CIRM-funded ($2.4 million) study conducted by Dr. Deepak Srivastava and his team at the Gladstone Institutes, a potential drug candidate for heart valve disease was discovered. It has been found to function in both human cells and animals and is ready to move toward a clinical trial.

For this study, Dr. Srivastava and his team looked for drug-like molecules that had the potential to correct the mechanism in heart valve disease that leads to gradual hardening. To do so, the team first had to determine the network of genes that are turned on or off in the diseased cells.

Once the genes were identified, they used an artificial intelligence method to train a machine learning program to detect whether a cell was healthy or diseased based on the network of genes identified. They proceeded to treat the diseased human cells with nearly 1,600 molecules in order to identify any drugs that would cause the machine learning program to reclassify diseased cells as healthy. The team successfully identified a few molecules that could correct diseased cells back to a healthy state.

Dr. Srivastara then collaborated with Dr. Anna Malashicheva, from the Russian Academy of Sciences, who had collected valve cells from over 20 patients at the time of surgical replacement. Using the valve cells that Dr. Malashicheva had collected, Dr. Srivastara and his team conducted a “clinical trial in a dish” in which they tested the molecules they had previously identified in the cells from the 20 patients with aortic valve hardening. The results were remarkable, as the molecule that seemed most effective in the initial study was able to restore these patients’ cells as well.

The final step taken was to determine whether the drug-like molecule would actually work in a whole, living organ. To do this, Dr. Srivastava and his team did a “pre-clinical trial” in a mouse model of the disease. The team found that the therapeutic candidate could successfully prevent and treat aortic valve disease. In young mice who had not yet developed the disease, the therapy prevented the hardening of the valve. In mice that already had the disease, the therapy was able to halt the disease and, in some cases, reverse it. This finding is especially important since most patients aren’t diagnosed until hardening of the heart valve has already begun.

Dr. Deepak Srivastava (left) and Dr. Christina V. Theodoris (right)
Image Credit: Gladstones Institute

Dr. Christina V. Theodoris, a lead author of the study who is now completing her residency in pediatric genetics, was a graduate student in Dr. Srivastava’s lab and played a critical role in this research. Her first project was to convert the cells from patient families into induced pluripotent stem cells (iPSCs), which have the potential of becoming any cell in the body. The newly created iPSCs were then turned into cells that line the valve, allowing the team to understand why the disease occurs. Her second project was to make a mouse model of calcific aortic valve disease, which enabled them to start using the models to identify a therapy.

In a press release from Gladstone Institutes, Dr. Theodoris, discusses the impact of the team’s research.

“Our strategy to identify gene network–correcting therapies that treat the core disease mechanism may represent a compelling path for drug discovery in a range of other human diseases. Many therapeutics found in the lab don’t translate well to humans or focus only on a specific symptom. We hope our approach can offer a new direction that could increase the likelihood of candidate therapies being effective in patients.”

In the same press release, Dr. Srivastava emphasizes the scientific advances that have driven the team’s research to this critical point.

“Our study is a really good example of how modern technologies are facilitating the kinds of discoveries that are possible today, but weren’t not so long ago. Using human iPSCs and gene editing allowed us to create a large number of cells that are relevant to the disease process, while powerful machine learning algorithms helped us identify, in a non-biased fashion, the important genes for distinguishing between healthy and diseased cells.”

The full results of this study were published in Science.

Stem Cell All-Stars, All For You

goldstein-larry

Dr. Larry Goldstein, UC San Diego

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.

BotaDaniela2261

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.

srivastava-deepak

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

Daniela Bota: UC Irvine talking about COVID-19 research

Deepak Srivastava: Gladsone Institutes, talking about heart stem cells

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.

We look forward to seeing you there.

Scientists at Gladstone and UCSF form two new research institutes

Dr. Melanie Ott (left) and Dr. Alexander Marson (right)
Image Credit: Gladstone Institutes

In a previous blog post, we talked about how scientists at the Gladstone Institutes have shifted their current operations towards helping with the current coronavirus pandemic. Now scientists at Gladstone and U.C. San Francisco have formed two new research institutes to broaden its impact on unsolved diseases such as COVID-19.

One of these institutes is the Gladstone Institute of Virology and will be lead by Dr. Melanie Ott. The immediate focus of this newly formed institution will be the current coronavirus pandemic. Additionally, it will focus on searching for new therapies against future infectious diseases. The Gladstone Institute of Virology will focus on how viruses interact with human cells to cause disease and how to intervene in that process. Dr. Ott’s goal is to identify pathways these viruses use to infect human cells as a way to develop innovative treatments.

In a press release from Gladstone Institutes, Dr. Ott talks about the goal of her work in more detail.

“Contrary to the current strategy of combining several drugs to treat one virus, we want to develop one drug against multiple viruses. As antibiotic resistance becomes an increasingly urgent problem, we will also delve into how we can use viruses as therapeutics, which involves using viruses against themselves or to fight bacteria.”

The second institute is a collaboration between UCSF and Gladstone Institutes and is called the Gladstone-UCSF Institute of Genomic Immunology. It will be lead by Dr. Alexander Marson and will combine the study of genomics and immunology to develop new therapies. One of the primary goals will be to understand the role that genetics play in human immune cells. By manipulating these cells, the immune system could potentially be altered to treat cancer, infectious diseases, autoimmune diseases, and even neurological conditions such as Alzheimer’s.

In the same press release from Gladstone Institutes, Dr. Marson discusses the importance these collaborations hold for pushing scientific innovation.

“These rapidly advancing fields are starting to converge in ways that are too big for any single lab to take on. The impetus to start a new institute was the realization that we need to create an ecosystem to bring together people with different perspectives to think about transformative opportunities for how patients can be treated in the future.”