stem cell Archives - Sanford Burnham Prebys

Tag: stem cell

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Using stem cells to study the biochemistry of learning

AuthorMiles Martin
Date

August 18, 2022

Neural networks grown from human stem cells

A method for studying human neurons could help researchers develop approaches for treating Alzheimer’s, schizophrenia and other neurological diseases

Researchers from the Conrad Prebys Center for Chemical Genomics have developed a procedure to use neurons derived from human stem cells to study the biological processes that control learning and memory. The method, described in Stem Cell Reports, uses electrodes to measure the activity of neuronal networks grown from human-induced pluripotent stem cells (iPSCs). The procedure tracks how synapses—the connections between neurons—strengthen over time, a process called long-term potentiation (LTP).

“Impaired long-term potentiation is thought to be central to many neurological diseases, including Alzheimer’s, addiction and schizophrenia,” says senior author Anne Bang, PhD, director of Cell Biology at the Prebys Center. “We’ve developed an approach to study this process in human cells much more efficiently than current methods, which could help trigger future breakthroughs for researchers working on these diseases.”

LTP helps our brain encode information, which is what makes it so critical for learning and memory. Impairment of LTP is thought to contribute to neurological diseases, but it has proven difficult to verify this hypothesis in human cells.

LTP helps our brain encode information, which is what makes it so critical for learning and memory. Impairment of LTP is thought to contribute to neurological diseases, but it has proven difficult to verify this hypothesis in human cells.

Anne Bang, PhD, director of Cell Biology at the Prebys Center.

“LTP is such a fundamental process,” says Bang. “But the human brain is hard to study directly because it’s so inaccessible. Using neurons derived from human stem cells helps us work around that.”

Although LTP can be studied in animals, these studies can’t easily account for some of the more human nuances of neurological diseases.

“A powerful aspect of human stem cell technology is that it allows us to study neurons produced from patient stem cells. Using human cells with human genetics is important in these types of tests because many neurological diseases have complex genetics underpinning them, and it’s rarely just one or two genes that influence a disease,” adds Bang.

To develop the method, first author and Prebys Center staff scientist Deborah Pré, PhD, grew networks of neurons from healthy human stem cells, added chemicals known to initiate LTP and then used electrodes to monitor changes in neuronal activity that occurred throughout the process.

The method can run 48 tests at once, and neurons continue to exhibit LTP up to 72 hours after the start of the experiment. These are distinct advantages over other approaches, which can often only observe parts of the process and are low throughput, which can make getting results more time consuming.

For this study, the researchers used neurons grown from healthy stem cells to establish a baseline understanding of LTP. The next step is to use the approach on neurons derived from patient-derived stem cells and compare these results to the baseline to see how neurological diseases influence the LTP process.

“This is an efficient method for interrogating human stem cell–derived neurons,” says Bang. “Doing these tests with patient cells could open doors for researchers to discover new ways of treating neurological diseases.”

Institute News

Boosting immunotherapy in aggressive brain cancer

AuthorMiles Martin
Date

November 3, 2021

Blue and orange illustration of human brain against black background

Researchers from Sanford Burnham Prebys have collaborated the University of Pittsburgh Cancer Institute to reveal a new approach to enhance the effects of immunotherapy in glioblastoma, one of the most aggressive and treatment-resistant forms of brain cancer.

The study, published recently in Cancer Discovery, describes a novel method to ‘turn off’ cancer stem cells—the malignant cells that self-renew and sustain tumors—enabling the body’s own defense system to take charge and destroy tumors.

“Tumors are more than just masses of cells—each one is a complex system that relies on a vast network of chemical signals, proteins and different cell types to grow,” says senior author Charles Spruck, PhD, an assistant professor at Sanford Burnham Prebys. “This is part of why cancer is so difficult to treat, but it also presents us with opportunities to develop treatment strategies that target the machinery powering tumor cells rather than trying to destroy them outright.”

Glioblastoma is an extremely aggressive form of cancer that affects the brain and the spinal cord. Occurring more often in older adults and forming about half of all malignant brain tumors, glioblastoma causes worsening headaches, seizures and nausea. And unfortunately for the thousands of people who receive this diagnosis each year, glioblastoma is most often fatal.

“We haven’t been able to cure glioblastoma with existing treatment methods because it’s just too aggressive,” says Spruck. “Most therapies are palliative, more about reducing suffering than destroying the cancer. This is something we hope our work will change.”

Immune checkpoint inhibitors—which help prevent cancer cells from hiding from the immune system—can be effective for certain forms of cancer in the brain, but their results in glioblastoma have been disappointing. The researchers sought a way to improve the effects of these medications.

“Modern cancer treatment rarely relies on just one strategy at a time,” says Spruck. “Sometimes you have to mix and match, using treatments to complement one another.”

The researchers used genomic sequencing to investigate glioblastoma stem cells. These cells are the source of the rapid and consistent regeneration of glioblastoma tumors that make them so difficult to treat.

The team successfully identified a protein complex called YY1-CDK9 as essential to the cells’ ability to express genes and produce proteins. By modifying the activity of this protein complex in the lab, the team was able to improve the effectiveness of immune checkpoint inhibitors in these cells. 

“Knocking out this transcription machinery makes it much more difficult for the cells to multiply” says Spruck. “They start to respond to chemical signals from the immune system that they would otherwise evade, giving immunotherapy a chance to take effect.” 

While the approach will need to be tested in clinical settings, the researchers are optimistic that it may provide a way to improve treatment outcomes for people with glioblastoma. 

“What our results tell us is that these cells are targetable by drugs we already have, so for patients, improving their treatment may just be a matter of adding another medication,” adds Spruck. “For a cancer as treatment-resistant as glioblastoma, this is a great step forward.”

Institute News

Stem cell Prop. 71 saved lives. It’s successor, Prop. 14, will save more—maybe yours.

AuthorEvan Y. Snyder, MD, PhD
Date

November 2, 2020

Evan Snyder photo

Those who argue that Proposition 14—which will continue to fund stem cell research that foresightful Californians approved in 2004 via Proposition 71—is no longer necessary unfortunately have a narrow view of stem cell science.

All one needs to do is to think back to our world before California’s emergence as the “Mecca” for this science to realize how different—for the better —we are and can continue to be in this state.

These accomplishments extend beyond the numbers. Yes, CIRM has enabled more than 90 clinical trials involving more than 4,000 patients with more than 75 diseases; produced more than 800 patent applications; published more than 3,000 contributions to scientific knowledge in the form of peer-reviewed papers; and created numerous new jobs, companies and programs that drew tax-paying citizens to California from other states.

And yes, there have been actual cures. Bone marrow transplantation is a stem cell-based therapy that has the ability to cure conditions such as sickle cell anemia, “bubble baby” disease, certain cancers, metabolic diseases, even HIV. CAR T-cell therapy, one of the newest and most exciting cell-based treatments against a range of cancers, is a stem cell-based therapy. Novel drugs can now cure formerly incurable cancers because they attack cancer stem cells. 

And indeed, there are now treatments on the horizon for devastating maladies. People living with spinal cord injury, brain conditions such as multiple sclerosis, Parkinson’s disease, and stroke; eye conditions such as macular degeneration; psychiatric disorders; diabetes; even COVID-19, can hope for a better future because of stem cells’ ability either to address the problem directly, or to make therapeutic “caregiver” molecules, or to better model the disease(s) to enable novel drug discovery. 

However, stem cell biology’s most profound legacy is likely how it has changed society’s vision of itself. When it comes to our life, we have come to view ourselves not as rigid beings, but flexible, malleable creatures who accept no boundaries—because we know the repairing power of stem cells. 

Alzheimer’s patients are no longer institutionalized but rather placed in enriched environments. Children with autism are given aggressive early intervention. Parkinson’s patients are taught ballroom dancing. 

We are encouraged to exercise into old age and to take up challenging tasks to keep our brains sharp. All of these notions are stem cell biology’s contribution to our very nature and our perceptions of being human.

Indeed, passing Proposition 14 may have the greatest immediate and lasting impact on most Californians’ well-being than any other measure on the ballot. And our use of these life-saving strategies is once again being threatened in Washington D.C., just as it was in 2004. Please continue this life-saving research by voting Yes on Proposition 14. 

Evan Snyder, MD, PhD, is professor and director of the Center for Stem Cells and Regeneration program at Sanford Burnham Prebys. He is regarded as one of the “fathers of the stem cell field” and was named a “stem cell revolutionary” by Forbes. Snyder was the first to isolate human neural stem cells, which will soon be tested as a treatment for premature newborns, and served two terms as Chairman of the FDA’s Cellular, Tissue, and Gene Therapy Advisory Committee. His lab explores the basic biology of stem cells and their therapeutic potential, particularly for brain disorders such as Parkinson’s disease and bipolar disorder.

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Scientists “turn back time” on cancer using new stem cell reprogramming technique

AuthorMonica May
Date

August 21, 2020

human cells

Discovery opens new research avenues that may help catch cancer early and identify potential preventive treatments

Scientists at Sanford Burnham Prebys Medical Discovery Institute have reprogrammed cancer cells back into their pre-cancer identity—opening new doors for studying how cancer develops and how it might be prevented. The research, published in Stem Cell Reports, may lead to tests that identify cancer early on, when it can be more easily treated, and uncover preventive treatments that stop cancer before it starts.

“We believe we have been able to contribute to one of the major goals of modern cancer research: creating next-generation models for studying how cancer develops from its earliest state,” says Evan Snyder, MD PhD, professor and director of the Center for Stem Cells & Regenerative Medicine at Sanford Burnham Prebys and senior author of the study. “We essentially took an adult cancer that has accumulated many mutations and pushed it back to the earliest stages of development, allowing us to emulate a tumor’s premalignant state. Then we watched cancer emerge from normal cells before our eyes.”

Turning back the clock on cancer 

In the study, the scientists set out to transform cells from anaplastic thyroid tumors—an aggressive, fast-growing cancer that is nearly always diagnosed at late stages—into induced pluripotent stem cells (iPSCs). These cells model the embryonic cells that are present at the earliest stages of human development and can become any cell in the body. While iPSCs are used today to create unlimited supplies of cells for research and therapeutic purposes—usually to correct abnormalities—the scientists recognized that tumor-derived iPSCs could be used to study the development of cancer.

However, this feat turned out to be easier said than done. The standard reprogramming method didn’t work, requiring the researchers to hunt for a different method that would induce the cancer cells to reset. Inhibiting a protein called RAS was the key ingredient that coaxed these thyroid cancer cells to become normal iPSC cells.

“We have named the pathway that is critical for making a cancer cell act as if it were a normal cell its ‘reprogram enablement factor,’” explains Snyder. “That factor will likely be different for every cancer and, in fact, may help in defining that cancer type.

“For this cancer type, which we examined in our study as a proof-of-concept, the reprogram enablement factor turned out to be blunting an overactive RAS pathway,” Snyder continues. “Our results suggest that losing control of RAS was the ‘big bang’ for this cancer—the very first event that leads to out-of-control cell growth and development of a tumor.”

The scientists next plan to reprogram additional cancers—including brain and lung cancer—into iPSCs to determine their “reprogram enablement factors.” If successful, they will next map the molecular changes that occur immediately before and after the tumors develop, which could reveal early signals of cancer and new preventive or early treatment measures.

“Unlike other cells, cancer cells are notoriously resistant to reprogramming,” says Snyder. “Our study is the first to successfully reprogram cancer cells into completely normal iPSCs, which opens new doors for cancer research.”

A team effort

The first author of the study is Yanjun Kong of Sanford Burnham Prebys and Shanghai Jiao Tong University. Yang Liu of Sanford Burnham Prebys is a co-corresponding author. Additional study authors include Ryan C. Gimple of UC San Diego; Rachael N. McVicar, Andrew P. Hodges and Jun Yin of Sanford Burnham Prebys; and Weiwei Zhan of Shanghai Jiao Tong University.

This study was funded by the Stem Cell Research Center & Core Facility at Sanford Burnham Prebys and by the China Scholarship Council (201606230202). The study’s DOI is 10.1016/j.stemcr.2020.07.016.

Institute News

First supercentenarian-derived stem cells created

AuthorMonica May
Date

March 19, 2020

telomere DNA illustration

Advance primes scientists to unlock the secrets of healthy aging.

People who live more than 110 years, called supercentenarians, are remarkable not only because of their age, but also because of their incredible health. This elite group appears resistant to diseases such as Alzheimer’s, heart disease and cancer that still affect even centenarians. However, we don’t know why some people become supercentenarians and others do not.

Now, for the first time, scientists have reprogrammed cells from a 114-year-old woman into induced pluripotent stem cells (iPSCs). The advance, completed by scientists at Sanford Burnham Prebys and AgeX Therapeutics, a biotechnology company, enables researchers to embark on studies that uncover why supercentenarians live such long and healthy lives. The study was published in Biochemical and Biophysical Research Communications.

“We set out to answer a big question: Can you reprogram cells this old?” says Evan Snyder, MD, PhD, professor and director of the Center for Stem Cells and Regenerative Medicine at Sanford Burnham Prebys, and study author. “Now we have shown it can be done, and we have a valuable tool for finding the genes and other factors that slow down the aging process.”

In the study, the scientists reprogrammed blood cells from three different people—the aforementioned 114-year-old woman, a healthy 43-year-old individual and an 8-year-old child with progeria, a condition that causes rapid aging—into iPSCs. These cells were then transformed into mesenchymal stem cells, a cell type that helps maintain and repair the body’s structural tissues—including bone, cartilage and fat.

The researchers found that supercentenarian cells transformed as easily as the cells from the healthy and progeria samples. As expected, telomeres—protective DNA caps that shrink as we age—were also reset. Remarkably, even the telomeres of the supercentenarian iPSCs were reset to youthful levels, akin to going from age 114 to age zero. However, telomere resetting in supercentenarian iPSCs occurred less frequently compared to other samples—indicating extreme aging may have some lasting effects that need to be overcome for more efficient resetting of cellular aging.

Now that the scientists have overcome a key technological hurdle, studies can begin that determine the “secret sauce” of supercentenarians. For example, comparing muscle cells derived from the healthy iPSCs, supercentenarian iPSCs and progeria iPSCs would reveal genes or molecular processes that are unique to supercentenarians. Drugs could then be developed that either thwart these unique processes or emulate the patterns seen in the supercentenarian cells.

“Why do supercentenarians age so slowly?” says Snyder. “We are now set to answer that question in a way no one has been able to before.”

The senior author of the paper is Dana Larocca, PhD, vice president of Discovery Research at AgeX Therapeutics, a biotechnology company focused on developing therapeutics for human aging and regeneration; and the first author is Jieun Lee, PhD, a scientist at AgeX.

Additional authors include Paola A. Bignone, PhD, of AgeX; L.S. Coles of Gerontology Research Group; and Yang Liu of Sanford Burnham Prebys and LabEaze. The work began at Sanford Burnham Prebys when Larocca, Bignone and Liu were members of the Snyder lab.

The study’s DOI is 10.1016/j.bbrc.2020.02.092.

Institute News

SBP supports opening of stem cell exhibit at the Reuben H. Fleet Science Center

Authorjmoore
Date

January 29, 2016

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Pamela Itkin-Ansari, PhD, adjunct assistant professor in the Development, Aging, and Regeneration Program at SBP, participated in the grand opening event for the Super Cells exhibit at the Fleet on Jan. 28. She served as an expert on the current understanding of stem cells, answering questions and explaining what stem cell researchers do.

The Super Cells exhibit, on view at the Fleet through May 1, immerses visitors in the world of stem cells, illustrating how they give rise to the whole body and how they keep us healthy by re-building tissue.

The display was produced by the Sherebrooke Musuem of Nature and Science (Quebec, Canada), in partnership with the California Institute for Regenerative Medicine (CIRM), Catapult Cell Therapy and the Centre for Commercialization of Regenerative Medicine, and supported by EuroStemCell.

Itkin-Ansari is one of several SBP investigators working to harness the power of stem cells to treat disease. Faculty in SBP’s Center for Stem Cell Biology and Regenerative Medicine collaborate to develop new treatments for a wide spectrum of disorders, including Alzheimer’s disease, spinal cord injury, heart disease, and diabetes.

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Q&A with MS patient advocate Denise Boucher

Authorrbruni
Date

May 21, 2015

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Denise Boucher is a vibrant, gregarious, and engaging individual, with an easy smile and a quick wit. When you meet her the for the first time and feel her infectious energy, it’s hard to imagine that she has endured a nearly 20-year long battle with multiple sclerosis (MS) that has taken most of her sight and her ability walk.

Despite these challenges, Denise does not let MS stop her from living life on her terms. She is an active, passionate MS advocate who spends her time educating others about the degenerative disease and supporting fellow survivors.

On March 24, Denise visited the Institute’s La Jolla campus for the very first time as part of the National Multiple Sclerosis Society’s (NMSS) MS Awareness Month to learn more about how our researchers are making advancements in the fight against this immune-mediated disease.

We sat down with her after her visit to hear some highlights from her time at the Institute.

Q: Tell us a little about yourself and how you became a research advocate for MS?

A: When I was 25, I moved to Arizona to continue my dream career in advertising. Suddenly, strange things began to happen, including numbness on one side of my body and later blindness in one eye.

My eyesight, which I’d never had any problems with before, was becoming an increasing issue. I later learned that this is a common early symptom for MS patients. It progressed very quickly from there and it wasn’t long before my doctors diagnosed me with MS. Shortly after, I lost most of the vision in my other eye.

It’s hard to explain what a diagnosis like that means to you when you’re 25, but I tried to keep moving forward with my life and not let it derail my career, or impact my ability stay positive and enjoy my life. After a while, my symptoms progressed and I knew that things had to change. I managed to continue working in advertising for many years, but after 21 years I ended my career to focus on my health.

It was a very difficult time, to say the least, but I made the best of it. I became an advocate along the way to help others in a similar situation and share what I’ve learned with them. It’s my way to give back, stay active, positive, and move forward with my life.

Q. When you hear about research happening at Sanford-Burnham, what does it mean to you?

A. When I was first invited to join the MS tour I was so, so excited. This was really an opportunity of a lifetime, in my opinion, to visit with scientists and learn more about what they do and the impact that they could have on potential treatments.

Just being at Sanford-Burnham and seeing what’s going on lets me know that the future will be easier for others. Seeing the dedicated scientists at Sanford-Burnham and hearing their passion for curing this disease, fills me with hope. And that means a lot.

Q. What were some of your takeaways from your visit to the Institute?

This visit meant more than I ever expected. Truthfully. You read and hear about research, but you rarely have the opportunity connect what scientists are doing to the potential end result. When you’re here on campus, talking to the scientists—who are so passionate about their work—it becomes much clearer how their research is directly correlated to future medicines.

I was also blown away by how collaborative the Institute is. I had no idea how many different departments work together with so many different specialties in order to make the discoveries that they do. The whole visit was incredibly enlightening.

Q. Why do you support early-stage research, like Dr. Ranscht’s? Dr. Ranscht is an incredible woman and her passion for curing MS is palpable. She cares and is dedicating her life to finding innovative new approaches to tackling this disease. How could I not support that?

Without people and research like hers, the next big discovery won’t be found and next-generation medicines can’t be developed. Early-stage research is imperative to our future.

 

If you would like to arrange a visit to the Institute to learn more about our research, please contact Sandy Hanna at Shanna@sanfordburnham.org, or call 858-795-5056.

Institute News

New study sheds light on cancer stem cell regulation

Authorsgammon
Date

February 5, 2015

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Researchers at Sanford-Burnham have discovered a precise stem cell signaling process that can lead to intestinal tumors if disrupted. The findings add to our understanding of how stem cells give rise to tumors and identify specific stem cell molecules that may be targeted to prevent the onset, progression, and recurrence of intestinal cancers. The results of the study appear online in Cell Reports today. Continue reading “New study sheds light on cancer stem cell regulation”