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.
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.
The global pandemic has highlighted many of the inequities in our health care system, with the virus hitting communities of color the hardest. That has led to calls for greater diversity, equity and inclusion at every level of scientific research and, ultimately, of medical care. A recently released article in the journal Nature Cell Biology, calls for “new models for basic and disease research that reflect diverse ancestral backgrounds and sex and ensure that diverse populations are included among donors and research participants.”
The authors of the article are Dr. Maria T. Millan, CIRM’s President & CEO; Rick Horwitz Senior Advisor and Executive Director, Emeritus, Allen Institute for Cell Science; Dr. Ekemini Riley, President, Coalition for Aligning Science; and Dr. Ruwanthi N. Gunawardane, Executive Director of the Allen Institute for Cell Science.
Dr. Maria Millan, CIRM’s President & CEO, says we need to make these issues a part of everything we do. “At CIRM we have incorporated the principles of promoting diversity, equity and inclusion in our research funding programs, education programs and future programs. We believe this is essential to ensure that the therapies our support helps advance will reach all patients in need and in particular communities that are disproportionately affected and/or under-served.”
The article highlights how, in addition to cultural, environmental, and socioeconomic factors, genetic factors also appear to play a role in the way disease affects different people. For example, 50 percent of people in South Asia have genetic traits that increases their risk for severe COVID-19, in contrast only 16 percent of Europeans have those traits.
But while some studies have shown how African American men are at greater risk for prostate cancer than white men, most of the research in this and other areas has been done on white populations of European ancestry. Efforts are already underway to change these disparities. For example, the National Institutes of Health (NIH) has sponsored the All of Us Research Program, which is inviting one million people across the U.S. to help build one of the most diverse health databases in history.
The article in Nature Cell Biology stresses the need to account for diversity at the individual molecular, cellular and tissue level. The authors make the point that diversity in those taking part in clinical trials is essential, but equally essential is that diverse biology is accounted for in the scientific work that leads to the development of potential therapies in order to increase the likelihood of success.
That’s why the authors of the article say: “If we are to truly understand human biology, address health disparities, and personalize our treatments, we need to go beyond our important, ongoing efforts in addressing diversity and inclusion in the workforce and the delivery of healthcare. We need to improve the data we generate by including diverse populations among donors and research participants. This will require new models and tools for basic and disease research that more closely reflect the diversity of human tissues, across diverse donor backgrounds.”
“Greater diversity in biological studies is not only the right thing to do, it is crucial to helping researchers make new discoveries that benefit everyone,” said Ru Gunawardane, Executive Director of the Allen Institute for Cell Science.
To do this they propose creating “a suite” of research cells, such as human induced pluripotent stem cell (hiPSC) lines from a diverse group of individuals to reflect the racial, ethnic and gender composition of the population. Human iPSCs are cells taken from any tissue (usually skin or blood) from a child or adult that have been genetically modified to behave like an embryonic stem cell. As the name implies, these cells are pluripotent, which means that they can become any type of adult cell.
CIRM has already created one version of what this suite would look like, through its iPSC Repository, a collection of more than 2,600 hiPSCs from individuals of diverse ancestries, including African, Hispanic, Native American, East and South Asian, and European. The Allen Institute for Cell Science also has a collection that could serve as a model for this kind of repository. Its collection of over 50 hiPSC
lines have been thoroughly analyzed on both a genomic and biological level and could also be broken down to include diversity in donor ethnicity and sex.
Currently researchers use cells from different lines and often follow very different procedures in using them, making it hard to compare results from one study to another. Having a diverse and well defined collection of research cells and cell models that are created by standardized procedures, could make it easier to compare results from different studies and share knowledge within the scientific community. By incorporating diversity in the very early stages of scientific research, the scientists and therapy developers gain a more complete picture of the biology disease and potential treatments.
The more you learn about COVID-19 the more there is to dislike about it. The global death toll from the virus is now more than five million and for those who survive there can be long-term health consequences. We know COVID can attack the lungs, heart and brain. Now we are learning it can also mess up your ears causing hearing problems, ringing in the ear (tinnitus) and leave you dizzy.
Viral infections are a known cause of hearing loss and other kinds of infection. That’s why, before the pandemic started, Dr. Konstantina Stantovic at Massachusetts Eye and Ear and Dr. Lee Gherke at MIT had been studying how and why things like measles, mumps and hepatitis affected people’s hearing. After COVID hit they heard reports of patients experiencing sudden hearing loss and other problems, so they decided to take a closer look.
They took cells from ten patients who had all experienced some hearing or ear-related problems after testing positive for COVID and, using the iPSC method, turned those cells into the kind found in the inner ear including hair cells, supporting cells, nerve fibers, and Schwann cells.
They then compared those to cells from patients who had similar hearing issues but who had not been infected with COVID. They found that the hair and Schwann cells both had proteins the virus can use to infect cells. That’s important because hair cells help with balance and the Schwann cells play a protective role for neuronal axons, which help different nerve cells in the brain communicate with each other.
In contrast, some of the other cells in the inner ear didn’t have those proteins and so were protected from COVID.
In a news release Dr. Stankovic says it’s not known how many people infected with COVID experienced hearing issues. “Initially this was because routine testing was not readily available for patients who were diagnosed with COVID, and also, when patients were having more life-threatening complications, they weren’t paying much attention to whether their hearing was reduced or whether they had tinnitus. We still don’t know what the incidence is, but our findings really call for increased attention to audio vestibular symptoms in people with Covid exposure.”
The doctors are not sure how the virus gets into the inner ear but speculate that it may enter through the Eustachian tube, that’s a small passageway that connects your throat to your middle ear. When you sneeze, swallow, or yawn, your Eustachian tubes open, preventing air pressure and fluid from building up inside your ear. They think that might allow particles from the nose to spread to the ear.
MRI section of a brain affected by ALS with the front section of the brain highlighted
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a nasty disease that steadily attacks nerve cells in the brain and spinal cord. It’s pretty much always fatal within a few years. As if that wasn’t bad enough, ALS also can overlap with a condition called frontotemporal dementia (ALS/FTD). Together these conditions cause devastating symptoms of muscle weakness along with changes in memory, behavior and personality.
Now researchers at Cambridge University in the UK have managed to grow groups of cells called “mini-brains” that mimic ALS/FTD and could lead to new approaches to treating this deadly combination.
We have written about these mini-brains before. Basically, they are created, using the iPSC method, that takes skin or blood cells from a patient with a particular condition, in this case ALS/FTD, and turns them into the kind of nerve cells in the brain affected by the disease. Because they came from someone who had ALS/FTD they display many of the characteristics of the disease and this gives researchers a great tool to study the condition.
This kind of approach has been done before and given researchers a glimpse into what is happening in the brains of people with ALS/FTD. But in the past those cells were in a kind of clump, and it wasn’t possible to get enough nutrients to the cells in the middle of the clump for the mini-brain to survive for long.
What is different about the Cambridge team is that they were able to create these mini-brains using thin, slices of cells. That meant all the cells could get enough nutrients to survive a long time, giving the team a better model to understand what is happening in ALS/FTD.
In a news release, Dr András Lakatos, the senior author of the study, said: “Neurodegenerative diseases are very complex disorders that can affect many different cell types and how these cells interact at different times as the diseases progress.
“To come close to capturing this complexity, we need models that are more long-lived and replicate the composition of those human brain cell populations in which disturbances typically occur, and this is what our approach offers. Not only can we see what may happen early on in the disease – long before a patient might experience any symptoms – but we can also begin to see how the disturbances change over time in each cell.”
Thanks to these longer-lived cells the team were able to see changes in the mini-brains at a very early stage, including damage to DNA and cell stress, changes that affected other cells which play a role in muscle movements and behavior.
Because the cells developed using the iPSC method are from a patient with ALS/FTD, the researchers were able to use them to screen many different medications to see if any had potential as a therapy. They identified one, GSK2606414, that seemed to help in reducing the build-up of toxic proteins, reduced cell stress and the loss of nerve cells.
The team acknowledge that these results are promising but also preliminary and will require much more research to verify them.
As of this moment, there are over two million podcasts and over 48 million episodes to listen to on your favorite listening device. If you’re a true crime enthusiast like me, you’ve surely heard of Casefile or one of the other 94 podcasts on the topic. But what if you’re looking for something a little less ghastly and a little more uplifting?
Dr. Daylon James, co-host of The Stem Cell Podcast
The Stem Cell Podcast is an informative and entertaining resource for scientists and science enthusiasts (or really, anyone) interested in learning about the latest developments in stem cell research.
Dr. Arun Sharma, co-host of The Stem Cell Podcast
On their latest episode, dynamic co-hosts and research scientists Dr. Daylon James and Dr. Arun Sharma sit down with our President & CEO, Dr. Maria Millan, to discuss the impact of California’s culture of innovation on CIRM, the challenge of balancing hope vs. hype in the context of stem cell research/therapies, and the evolution of the agency over the past 15 years.
Listen on as Dr. Millan highlights some of CIRM’s greatest victories and shares our mission for the future.
The second Wednesday in October is celebrated as Stem Cell Awareness Day. It’s an event that CIRM has been part of since then Governor Arnold Schwarzenegger launched it back in 2008 saying: ”The discoveries being made today in our Golden State will have a great impact on many around the world for generations to come.”
In the past we would have helped coordinate presentations by scientists in schools and participated in public events. COVID of course has changed all that. So, this year, to help mark the occasion we asked some people who have been in the forefront of making Governor Schwarzenegger’s statement come true, to share their thoughts and feelings about the day. Here’s what they had to say.
What do you think is the biggest achievement so far in stem cell research?
Dr. Jan Nolta
Jan Nolta, PhD., Director of the Stem Cell Program at UC Davis School of Medicine, and directs the new Institute for Regenerative Cures. “The work of Don Kohn and his UCLA colleagues and team members throughout the years- developing stem cell gene therapy cures for over 50 children with Bubble baby disease. I was very fortunate to work with Don for the first 15 years of my career and know that development of these cures was guided by his passion to help his patients.
Dr. Clive Svendsen
Clive Svendsen, PhD. Director, Board of Governors Regenerative Medicine Institute at Cedars-Sinai: “Without a doubt the discovery of how to make human iPSCs by Shinya Yamanaka and Jamie Thomson.”
When people ask you what kind of impact CIRM and stem cell research has had on your life what do you say?
Ronnie and his parents celebrating his 1st birthday. (Photo courtesy of Pawash Priyank)
Pawash Priyank and Upasana Thakur, parents of Ronnie,who was born with a life-threatening immune disorder but is thriving today thanks to a CIRM-funded clinical trial at UC San Francisco. “This is beyond just a few words and sentences but we will give it a shot. We are living happily today seeing Ronnie explore the world day by day, and this is only because of what CIRM does every day and what Stem cell research has done to humanity. Researchers and scientists come up with innovative ideas almost every day around the globe but unless those ideas are funded or brought to implementation in any manner, they are just in the minds of those researchers and would never be useful for humanity in any manner. CIRM has been that source to bring those ideas to the table, provide facilities and mechanisms to get those actually implemented which eventually makes babies like Ronnie survive and see the world. That’s the impact CIRM has. We have witnessed and heard several good arguments back in India in several forums which could make difference in the world in different sectors of lives but those ideas never come to light because of the lack of organizations like CIRM, lack of interest from people running the government. An organization like CIRM and the interest of the government to fund them with an interest in science and technology actually changes the lives of people when some of those ideas come to see the light of real implementation.
What are your biggest hopes for the future at UC Davis?
Jan Nolta, PhD: “The future of stem cell and gene therapy research is very bright at UC Davis, thanks to CIRM and our outstanding leadership. We currently have 48 clinical trials ongoing in this field, with over 20 in the pipeline, and are developing a new education and technology complex, Aggie Square, next to the Institute for Regenerative Cures, where our program is housed. We are committed to our very diverse patient population throughout the Sacramento region and Northern California, and to expanding and increasing the number of novel therapies that can be brought to all patients who need them.”
What are your biggest hopes for the future at Cedars-Sinai?
Clive Svendsen, PhD: “That young investigators will get CIRM or NIH funding and be leaders in the regenerative medicine field.”
What do you hope is the future for stem cell research?
Pawash Priyank and Upasana Thakur: “We always have felt good about stem cell therapy. For us, a stem cell has transformed our lives completely. The correction of sequencing in the DNA taken out of Ronnie and injecting back in him has given him life. It has given him the immune system to fight infections. Seeing him grow without fear of doing anything, or going anywhere gives us so much happiness every hour. That’s the impact of stem cell research. With right minds continuing to research further in stem cell therapy bounded by certain good processes & laws around (so that misuse of the therapy couldn’t be done) will certainly change the way treatments are done for certain incurable diseases. I certainly see a bright future for stem cell research.”
On a personal note what is the moment that touched you the most in this journey.
Jan Nolta, PhD: “Each day a new patient or their story touches my heart. They are our inspiration for working hard to bring new options to their care through cell and gene therapy.”
Clive Svendsen, PhD: “When I realized we would get the funding to try and treat ALS with stem cells”
How important is it to raise awareness about stem cell research and to educate the next generation about it?
Pawash Priyank and Upasana Thakur: “Implementing stem cell therapy as a curriculum in the educational systems right from the beginning of middle school and higher could prevent false propaganda of it through social media. Awareness among people with accurate articles right from the beginning of their education is really important. This will also encourage the new generation to choose this as a subject in their higher studies and contribute towards more research to bring more solutions for a variety of diseases popping up every day.”
Leica Picture of a brain organoid: courtesy National Institute of Allergy and Infectious Diseases, NIH
One of the biggest problems with trying to understand what is happening in a disease that affects the brain is that it’s really difficult to see what is going on inside someone’s head. People tend to object to you trying to open their noggin while they are still using it.
New technologies can help, devices such as MRI’s – which chart activity and function by measuring blood flow – or brain scans using electroencephalograms (EEGs), which measure activity by tracking electrical signaling and brain waves. But these are still limited in what they can tell us.
Enter brain organoids. These are three dimensional models made from clusters of human stem cells grown in the lab. They aren’t “brains in a dish” – they can’t function or think independently – but they can help us develop a deeper understanding of how the brain works and even why it doesn’t always work as well as we’d like.
Now researchers at UCLA’s Broad Center of Regenerative Medicine have created brain organoids that demonstrate brain wave activity similar to that found in humans, and even brain waves found in particular neurological disease.
The team – with CIRM funding – took skin tissue from healthy individuals and, using the iPSC method – which enables you to turn these cells into any other kind of cell in the body – they created brain organoids. They then studied both the physical structure of the organoids by examining them under a microscope, and how they were functioning by using a probe to measure brain wave activity.
In a news release Dr. Ranmal Samarasinghe, the first author of the study in the journal Nature Neuroscience, says they wanted to do this double test for a very good reason: “With many neurological diseases, you can have terrible symptoms but the brain physically looks fine. So, to be able to seek answers to questions about these diseases, it’s very important that with organoids we can model not just the structure of the brain but the function as well.”
Next, they took skin cells from people with a condition called Rhett syndrome. This is a rare genetic disorder that affects mostly girls and strikes in the first 18 months of life, having a severe impact on the individual’s ability to speak, walk, eat or even breathe easily. When the researchers created brain organoids with these cells the structure of the organoids looked similar to the non-Rhett syndrome ones, but the brain wave activity was very different. The Rhett syndrome organoids showed very erratic, disorganized brain waves.
When the team tested an experimental medication called Pifithrin-alpha on the Rhett organoids, the brain waves became less erratic and more like the brain waves from the normal organoids.
“This is one of the first tangible examples of drug testing in action in a brain organoid,” said Samarasinghe. “We hope it serves as a stepping stone toward a better understanding of human brain biology and brain disease.”
When someone has a stroke, the blood flow to the brain is blocked. This kills some nerve cells and injures others. The damaged nerve cells are unable to communicate with other cells, which often results in people having impaired speech or movement.
While ischemic and hemorrhagic strokes affect large blood vessels and usually produce recognizable symptoms there’s another kind of stroke that is virtually silent. A ‘white’ stroke occurs in blood vessels so tiny that the impact may not be noticed. But over time that damage can accumulate and lead to a form of dementia and even speed up the progression of Alzheimer’s disease.
Now Dr. Tom Carmichael and his team at the David Geffen School of Medicine at UCLA have developed a potential treatment for this, using stem cells that may help repair the damage caused by a white stroke. This was part of a CIRM-funded study (DISC2-12169 – $250,000).
Instead of trying to directly repair the damaged neurons, the brain nerve cells affected by a stroke, they are creating support cells called astrocytes, to help stimulate the body’s own repair mechanisms.
In a news release, Dr. Irene Llorente, the study’s first author, says these astrocytes play an important role in the brain.
“These cells accomplish many tasks in repairing the brain. We wanted to replace the cells that we knew were lost, but along the way, we learned that these astrocytes also help in other ways.”
The researchers took skin tissue and, using the iPSC method (which enables researchers to turn cells into any other kind of cell in the body) turned it into astrocytes. They then boosted the ability of these astrocytes to produce chemical signals that can stimulate healing among the cells damaged by the stroke.
These astrocytes were then not only able to help repair some of the damaged neurons, enabling them to once again communicate with other neurons, but they also helped another kind of brain cell called oligodendrocyte progenitor cells or OPCs. These cells help make a protective sheath around axons, which transmit electrical signals between brain cells. The new astrocytes stimulated the OPCs into repairing the protective sheath around the axons.
Mice who had these astrocytes implanted in them showed improved memory and motor skills within four months of the treatment.
And now the team have taken this approach one step further. They have developed a method of growing these astrocytes in large amounts, at very high quality, in a relatively short time. The importance of that is it means they can produce the number of cells needed to treat a person.
“We can produce the astrocytes in 35 days,” Llorente says. “This process allows rapid, efficient, reliable and clinically viable production of our therapeutic product.”
The next step is to chat with the Food and Drug Administration (FDA) to see what else they’ll need to do to show they are ready for a clinical trial.
One of the most amazing parts of an amazing job is getting to know the students who take part in CIRM’s SPARK (Summer Program to Accelerate Regenerative Medicine Knowledge) program. It’s an internship giving high school students, that reflect the diversity of California, a chance to work in a world-class stem cell research facility.
This year because of the pandemic I didn’t get a chance to meet them in person but reading the blogs they wrote about their experiences I feel as if I know them anyway.
The blogs were fun, creative, engaging and dealt with many issues, as well as stem cell and gene therapy research.
A common theme was how hard the students, many of whom knew little about stem cells before they started, had to work just to understand all the scientific jargon.
Areana Ramirez, who did her internship at UC Davis summed it up nicely when she wrote:
“Despite the struggles of taking over an hour to read a scientific article and researching what every other word meant, it was rewarding to know that all of the strain I had put on my brain was going toward a larger understanding of what it means to help others. I may not know everything about osteogenic differentiation or the polyamine pathway, but I do know the adversities that patients with Snyder-Robinson are facing and the work that is being done to help them. I do know how hard each one of our mentors are working to find new cures and are coming up with innovating ideas that will only help humankind.”
Lauren Ginn at City of Hope had the same experience, but said it taught her a valuable lesson:
“Make no mistake, searching for answers through research can sometimes feel like shooting arrows at a bulls-eye out of sight. Nonetheless, what CIRM SPARK has taught me is the potential for exploration that lies in the unknown. This internship showed me that there is so much more to science than the facts printed in textbooks.”
Rohan Upadhyay at UC Davis discovered that even when something doesn’t work out, you can still learn a lot:
“I asked my mentor (Gerhard Bauer) about what he thought had occurred. But unlike the textbooks there was no obvious answer. My mentor and I could only speculate what had occurred. It was at this point that I realized the true nature of research: every research project leads to more questions that need to be answered. As a result there is no endpoint to research. Instead there are only new beginnings.”
Melanie Nguyen, also at UC Davis, wrote her blog as a poem. But she saved the best part for the prose at the end:
“Like a hematopoietic stem cell, I have learned that I am able to pursue my different interests, to be multi-potential. One can indulge in the joys of biology while simultaneously live out their dreams of being an amateur poet. I choose it all. Similarly, a bone marrow stem cell can become whatever it may please—red, white, platelet. It’s ability to divide and differentiate is the source of its ingenuity. I view myself in the same light. Whether I can influence others with research, words, or stories, I know that with each route I will be able to make change in personalized ways.”
For Lizbeth Bonilla, at Stanford, her experiences transcended the personal and took on an even bigger significance:
“As a first-generation Mexican American, my family was thrilled about this internship and opportunity especially knowing it came from a prestigious institution. Unfortunately there is very little to no representation in our community in regards to the S.T.E.M. field. Our dreams of education and prosperity for the future have to be compromised because of the lack of support and resources. To maintain pride in our culture, we focus on work ethics and family, hoping it will be the next generations’ time to bring successful opportunities home. However, while this is a hope widely shared the effort to have it realized is often limited to men. A Latina woman’s success and interest in education are still celebrated, but not expected. As a first-generation Latina, I want to prove that I can have a career and hopefully contribute to raising the next leading generation, not with the hope that dreams are possible but to be living proof that they are.”
Reading the blogs it was sometimes easy to forget these are 16 and 17 year old students. They write with creativity, humor, thoughtfulness and maturity. They learned a lot about stem cell research over the summer. But I think they also learned a lot more about who they are as individuals and what they can achieve.
The Stem Cellar 