Gladstone Institutes

Gladstone Institutes is an independent, non-profit biomedical research organization whose focus is to better understand, prevent, treat and cure cardiovascular, viral and neurological conditions such as heart failure, HIV/AIDS and Alzheimer's disease.[1] Its researchers study these diseases using techniques of basic and translational science.[2] Another focus at Gladstone is building on the development of induced pluripotent stem cell technology by one of its investigators, 2012 Nobel Laureate Shinya Yamanaka, to improve drug discovery, personalized medicine and tissue regeneration.[3]

Gladstone Institutes

Established	1979
President	Deepak Srivastava
Faculty	30
Staff	450
Budget	$80 million
Location	1650 Owens St., San Francisco, CA , San Francisco , California , United States
Coordinates	37°46′03″N 122°23′39″W
Website	gladstoneinstitutes.org

Founded in 1979, Gladstone is affiliated with the University of California, San Francisco (UCSF) and is located in San Francisco, adjacent to UCSF’s Mission Bay campus. Approximately 450 staff members—including more than 300 scientists—work at Gladstone.

History

Gladstone Institutes was founded in 1979 as a research and training facility housed at San Francisco General Hospital. Under the leadership of Robert Mahley[4]—a cardiovascular scientist recruited from the National Institutes of Health[5]—the institutes was launched with a $8 million trust from the late commercial real estate developer, J. David Gladstone.[6]

In 1991, the institutes expanded its focus to include virology and immunology in response to the growing HIV/AIDS crisis. In 1998 it founded a third institute dedicated to studying neurological diseases.

In 2004 the Gladstone Institutes moved to a new facility in San Francisco’s Mission Bay, San Francisco neighborhood.[7] Two years later it founded a center dedicated to translating its biological discoveries into therapies. Three years later and together with Taube Philanthropies and the Koret Foundation, it founded the Taube-Koret Center for Huntington's Disease Research.

In 2010, Dr. Mahley stepped down in order to return to active research. R. Sanders “Sandy” Williams, Dean of the School of Medicine at Duke University, became Gladstone’s new president.[8]

In 2011, the S.D. Bechtel, Jr. Foundation helped launch the Center for Comprehensive Alzheimer's Disease Research, while the Roddenberry Foundation helped launch the Roddenberry Stem Cell Center for Biology and Medicine.[3] Also in 2011, the independent and philanthropic Gladstone Foundation formed with the mission of expanding the financial resources for the institutes.

Research Programs

Gladstone scientists focus on three main disease areas: cardiovascular disease, neurological disease and viral/immunological disease. Scientists working in all three disease areas use stem cell technology to advance the understanding, prevention, treatment and cure of disease.

Cardiovascular Disease

Gladstone cardiovascular scientists research the spectrum of cardiovascular disease—including congenital heart disease, congestive heart failure and related metabolic diseases such as diabetes. Scientists utilize developmental, chemical and stem cell biology approaches, as well as genomics techniques.

Current research programs include:

• Early heart development and congenital birth defects. Determining the biological steps in the embryonic development of the human heart to identify genes, RNAs or proteins that can be targeted to treat congenital heart disease.[9]
• Regenerative medicine to repair damaged hearts. Regenerating hearts by converting scar tissue into beating cardiac muscle. Creating heart cells from skin samples of patients with many cardiovascular diseases, such as calcification of the aortic valve, to test the safety and efficacy of new or existing drugs to treat or prevent the conditions.[10]
• Lipid metabolism. Defining the enzymes involved in triglyceride biosynthesis and the cell biology underlying lipid storage in cells, as a way to understand obesity-related illnesses—such as heart disease and diabetes—at the cellular level.
• Human evolution. Exploring the most rapidly evolving areas of the human genome to improve understanding of human disease and evolution.

Virology and Immunology

Virology and immunology research at Gladstone is focused primarily on three urgent challenges related to the HIV/AIDS epidemic: preventing viral transmission of HIV with drugs or a vaccine for those at risk of coming in contact with the virus, curing the millions of people who already live with HIV and restoring a normal lifespan to those who are HIV-positive—but who are dying earlier than their uninfected counterparts from diseases of aging.

In addition, the group studies hepatitis C, HTLV and the immunology of viral infections.

Current research programs include:

• “Treatment as prevention” strategies to blunt the rate of new HIV infections. Led by Gladstone scientists, the global iPrEx study showed how a daily pill could prevent HIV infection in people likely to be exposed; this study is currently in Phase-III clinical trials.[11]
• HIV integration. Investigating the mechanisms by which HIV integrates and replicates within human hosts—while evading the host immune system.
• HIV Pathogenesis. Investigating the mechanisms by which HIV infects and kills lymphoid CD4 T-cells, the fundamental cause of AIDS,[12][13] and the role of inflammation as a driver of HIV pathogenesis.[14][15][16]
• HIV latency. Investigating HIV latency as a member of the Martin Delaney Collaboratory—a consortium including academia, government and private industry. Latency occurs when HIV goes dormant and “hides” within cells, waiting for an opportunity to reemerge when antiretroviral medications are stopped.
• HIV and aging. Determining whether chronic, low-level inflammation associated with the disease—or the antiretroviral drugs used to treat HIV infection—are the major factors driving “accelerated aging” associated with HIV/AIDS.[17]
• Hepatitis C. Pathogenesis and targets for therapeutic intervention.[18] Looking for new biological targets for drugs that will attack the hepatitis C virus.
• Immunology of viral infection. Exploring the genomic regulation of viruses associated with cancer. Investigating why newborns and infants mount less effective immune responses to viruses than adults do.

Neurological Disease

Research at Gladstone focuses on major neurological diseases including: Alzheimer's disease, Parkinson's disease, frontotemporal dementia (FTD), Huntington's disease, amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease) and multiple sclerosis. This research incorporates animal models, electrophysiology, behavioral testing and automated high-throughput analyses. In addition, Gladstone investigators seek to accelerate the movement of basic science discoveries into clinical trials with efforts to bridge the so-called “Valley of Death.” The research features an emphasis on the “common threads” that link the various diseases and treatments for them.

Current research programs include:

• Alzheimer's disease and network disruption. Studying how damage to neurons affects their ability to communicate through chemical and electrical signals, which manifests as sub-clinical epileptic-like seizures. Discovered a link between this process and many of the deficits linked to Alzheimer's disease.[19]
• Alzheimer's disease and apolipoprotein E (apoE). Uncovered the molecular pathways that link apoE and Alzheimer's disease, and identifying new drugs that counteract detrimental effects of apoE4—the most important genetic risk factor for Alzheimer's.[5]
• Alzheimer's disease and tau. Understanding how lowering brain levels of the protein tau improves memory and other cognitive functions in mice genetically engineered to mimic Alzheimer's disease. Exploring therapeutic strategies to block tau's disease-promoting activities.[20]
• TDP-43. Studying TDP-43, another protein that may contribute to diverse neurodegenerative disorders.[21]
• Protein aggregates and their role in neurodegenerative disease. Helping to uncover the mystery behind protein aggregations—observed in Huntington's disease (inclusion bodies), Parkinson's disease (Lewy bodies), and Alzheimer's disease (neurofibrillary tangles and amyloid-beta plaques)—discovering that rather than being the culprit of neuronal death, these aggregates are part of a defense mechanism that safely sequesters toxin proteins in the brain, preventing them from wreaking further havoc.[22]
• Neural circuits involved in Parkinson’s disease. Investigating the network of brain cells that controls movement in order to figure out how its dysfunction leads to the symptoms of Parkinson’s disease.[23]
• Mitochondria and synaptic dysfunction. Studying mitochondria, the energy-producing subunits of cells, as their impairment appears to play an important role in multiple neurodegenerative conditions, including Alzheimer's, Parkinson’s and ALS.
• Autophagy. Researching how autophagy—a process by which cells eliminate abnormal proteins—can help prevent the destruction of brain cells. Discovering how the p75 neurotrophin receptor—a protein long known for its role in the development of brain cells—plays unexpected roles in both Alzheimer's and Type 2 diabetes.[24]
• Inflammation and neurodegenerative disease. Studying abnormal inflammatory responses by immune cells in the central nervous system—which may contribute to the progression of multiple sclerosis, neurodegenerative disorders and many other neurological conditions.
• Frontotemporal dementia (FTD). Showed a protein called progranulin prevents a type of brain cells from becoming "hyperactive." If not enough progranulin is available the hyperactivity can become toxic and result in extensive inflammation that kills brain cells and can lead to the development of FTD. Also showed that too much of another protein called TDP-43 plays a role in FTD disease progression. Importantly, Gladstone scientists have identified a means to suppress the toxic effects of TDP-43 for FTD and for another neurodegenerative disease: ALS.[25]

Stem Cell Technology

Many research areas build upon the stem cell work of Gladstone Senior Investigator Shinya Yamanaka. After completing his postdoctoral training at Gladstone, Yamanaka discovered induced pluripotent stem cell technology, by which ordinary differentiated adult cells (such as fibroblasts from skin) can be "reprogrammed" into a pluripotent state — i.e., a state similar to embryonic stem cells, which are capable of developing into virtually any cell type in the human body. His discovery of induced pluripotent stem cells, or iPS cells, has since revolutionized the fields of developmental biology, stem cell research and both personalized and regenerative medicine.[26] In 2012 Yamanaka was awarded the Nobel Prize in Physiology or Medicine.[27]

Since Yamanaka's 2006 discovery, scientists have made many advances in iPS technology and continue to conduct research in several areas of stem cell biology.

Current research programs include:[28]

• Reprogramming cardiac connective tissue located in the heart directly into beating cardiac muscle cells.[10]
• Discovering new ways to use chemical compounds to convert cells from one type into another.[29]
• Direct reprogramming of cells into neurons and neural precursor cells.[30]
• Using iPS cells to create human models to research solutions for Huntington's disease and Alzheimer's disease.
• Studying whether the retrotransposons (also known as “jumping genes”, because they move around within the chromosomes of a single cell) residing in our DNA become more active when a skin cell is reprogrammed into an iPS cell.
• Using iPS technology to create a new model for testing a vaccine for HIV/AIDS.

Translational Research

The Gladstone Center for Translational Research facilitates interactions between Gladstone scientists and the biomedical industry—including venture capitalists, biotech firms and large corporations. The Center’s primary goal is to translate the results of Gladstone’s basic science into therapeutics that help patients with cardiovascular, viral or neurological diseases.

Researchers

Researchers at the institute include:

• Deepak Srivastava—Regenerated the damaged hearts of mice by transforming cells that normally form scar tissue after a heart attack into beating heart-muscle cells. This discovery, now moving forward with pre-clinical trials, could one day change the way doctors treat heart attacks.[10]
• Shinya Yamanaka—Awarded the 2012 Nobel Prize in Physiology or Medicine for his discovery of how to transform ordinary adult skin cells into induced pluripotent stem cells (iPS cells) that, like embryonic stem cells, can then develop into other cell types.[31] Since he first announced this research in 2006 (in mice) and in 2007 (in humans), this breakthrough has since revolutionized the fields of cell biology and stem cell research, opening promising new prospects for the future of both personalized and regenerative medicine.[26]
• Katerina Akassoglou—Showed that the blood protein called fibrinogen plays a role in diseases of the central nervous system. Her studies suggest that molecular interactions between blood and the brain can be targets for therapeutic intervention in neurological diseases such as multiple sclerosis.[24]
• Sheng Ding—Discovered multiple “small molecules” or chemical compounds that can be used to generate iPS cells in the place of traditional reprogramming factors. Also made progress in the area of “partial reprogramming” in which cells are converted only part way to the pluripotent state before being instructed to become another cell type—a faster process that reduces the risk of these cells forming tumors as a result of the reprogramming process. These discoveries are a significant step towards better and more efficient human models for drug testing and development.[29]
• Steve Finkbeiner—Developed an automated, high-resolution imaging system called a ‘robotic microscope,’ and which can track neurons over long time periods of time. This invention has significantly improved our understanding of how neurodegenerative conditions such as Huntington’s destroy neurons.[22]
• Robert M. Grant—Led the global study, referred to as iPrEx, which in 2010 showed how an existing HIV/AIDS medication called Truvada could effectively be used to prevent the transmission of HIV in those likely to be exposed to the virus. This study is currently in Phase-III clinical trials. In July, the FDA approved Truvada as an HIV-preventative.[11]
• Warner C. Greene—Provided insight into the precise mechanisms of how HIV attacks the human immune system, and how small fibrils found in semen enhance the ability of HIV to infect cells—paving the way for the development of new ways to prevent the spread of the virus. Identifying pyroptosis as the predominant mechanism that causes the two signature pathogenic events in HIV infection––CD4 T-cell depletion and chronic inflammation. Identifying pyroptosis may provides novel therapeutic opportunities targeting caspase-1, which controls the pyroptotic cell death pathway.[32] Specifically, these findings could open the door to an entirely new class of “anti-AIDS” therapies that act by targeting the host rather than the virus.[16][33]
• Yadong Huang—Transformed skin cells into cells that develop on their own into an interconnected, functional network of brain cells. Such a transformation of cells may lead to better models for studying disease mechanisms and for testing drugs for devastating neurodegenerative conditions such as Alzheimer's disease.[30][34] In 2018 published an article in Nature Medicine about Apolipoprotein E(apoE) gene expression - pluripotent stem cell cultures from patients with Alzheimer's disease with the APOE-ε4 polymorphism (linked to Alzheimer's) were treated with a “structure corrector” that made the protein expressed similar to that of the APOE-ε3 allele.[35][36][37]
• Robert “Bob” W. Mahley — Established the importance of the protein apoE while working at the National Institutes of Health (NIH), later making significant contributions to science’s understanding of the critical role that apoE plays in heart disease and Alzheimer's disease.[5]
• Lennart Mucke—Discovered key mechanisms that underlie the specific dysfunctions in the brains of patients suffering from Alzheimer's disease, and helped identify novel therapeutic strategies to block these disease-causing mechanisms.[19]
• Katherine Pollard: Discovered short sequences of human DNA that have evolved rapidly since the human and ape lines diverged millions of years ago. Most of these fast-evolving sequences are genes that actually control other genes nearby. Many are located near genes that are active in the brain, and one appears to have a role in how the wrist and thumb develop in the fetus. These discoveries give us new insight not only into the evolutionary history of our species, but also into how genes control embryonic development—which gets us a step further to unraveling how to interrupt congenital defects.[38]
• R. Sanders Williams—While at Duke University, discovered key genes, proteins, and pathways involved in the development and proliferation of cardiac and skeletal muscle cells—giving researchers important insight into how a heart becomes a heart.[8]
• Jennifer Doudna — CRISPR gene editing pioneer, working to adapt the technology towards applications in biotechnology and medicine, including developing a rapid diagnostic test for COVID-19
• Melanie Ott — Ott's research program centers on understanding how viruses hijack their host's cells in order to better identify drug targets to prevent the spread of infection. She's worked on re-purposing drugs currently used to treat cancer by targeting a cell's epigenetic machinery towards more effectively treating HIV infections. She is now directing her research efforts towards addressing the COVID-19 pandemic.[39]

References

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7. Levy, Dan (2004-09-10). "Boost for biotech in S.F. / Gladstone Institutes to open Mission Bay research center". SFGate. Retrieved 2020-02-19.
8. Leuty, Ron (April 29, 2011). "Williams spins science into fundraising gold". www.bizjournals.com. Retrieved 2020-02-19.
9. Johnson, Carolyn. "Bay Area team's discovery could unlock origins of heart defects". ABC7 San Francisco.
10. Reversing a heart attack: scientists reprogram scar tissue into working muscle, Scientific American
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16. "Scientists Discover How Key Immune Cells Die During HIV Infection and Identify Potential Drug to Block AIDS". UC San Francisco.
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18. Herker, Eva; Harris, Charles; Hernandez, Céline; Carpentier, Arnaud; Kaehlcke, Katrin; Rosenberg, Arielle R.; Farese, Robert V.; Ott, Melanie (November 2010). "Efficient hepatitis C virus particle formation requires diacylglycerol acyltransferase-1". Nature Medicine. 16 (11): 1295–1298. doi:10.1038/nm.2238. ISSN 1546-170X. PMC 3431199. PMID 20935628.
19. Gladstone researchers find epilepsy drug that may work for Alzheimer's patients, San Francisco Business Times
20. Studies tie abnormal protein build-up to dementia, New York Times
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23. "Latest News, Diets, Workouts, Healthy Recipes - MSN Health & Fitness". healthyliving.msn.com.
24. NIH-funded Researchers Show Possible Trigger for MS Nerve Damage, ScienceNewsLine
25. Researchers Lasso TDP-43 With RNA Lariats, Alzheimer's Research Forum
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33. "Home".
34. Landhuis, Esther. "Could the "Alzheimer's Gene" Finally Become a Drug Target?".
35. "Researchers Fix Genetic Risk Factor of Alzheimer's in Human Brain Cells". 9 April 2018.
36. Chengzhong Wang, Ramsey Najm, Qin Xu, Dah-eun Jeong, David Walker, Maureen E. Balestra, Seo Yeon Yoon, Heidi Yuan, Gang Li, Zachary A. Miller, Bruce L. Miller, Mary J. Malloy & Yadong Huang. Gain of toxic Apolipoprotein E4 effects in Human iPSC-Derived Neurons Is Ameliorated by a Small-Molecule Structure Corrector. Nature Medicine, 2018 DOI: 10.1038/s41591-018-0004-z
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External links

• Official site