Gladstone Institutes

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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 / 37.7676°N 122.3941°W / 37.7676; -122.3941Coordinates: 37°46′03″N 122°23′39″W / 37.7676°N 122.3941°W / 37.7676; -122.3941
Website	gladstoneinstitutes.org

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]

Founded in 1979, Gladstone is academically affiliated with the University of California, San Francisco (UCSF), and located adjacent to UCSF's Mission Bay campus. The organization comprises five major institutes, as well as multiple centers focused on various areas of research.

The current president of the institute is Deepak Srivastava.

History[]

Gladstone Institutes was founded in 1979 as a research and training facility housed at San Francisco General Hospital. Under inagural president 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 2004 the Gladstone Institutes moved to a new facility in San Francisco's Mission Bay, San Francisco neighborhood.^[7]

Dr. Mahley stepped down as president in 2010 to return to active research, and was replaced by R. Sanders Williams (former Dean of the School of Medicine at Duke University). ^[8] Deepak Srivastava became the institute's third president in January 2018.^[9]

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.^{[citation needed]}

Research programs[]

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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, utilizing developmental, chemical, and stem cell biology approaches, as well as genomics techniques, across a variety of research programs and institutes. Their research has included:

• Determining the genetic factors of congenital birth defects in early heart development
• Studying vartious methods to repair damaged hearts, including creating heart cells from skin samples and converting scar tissue into muscle.^[10]
• Exploring human evolution and metabolism to understand the human genome, and illnesses at the cellular level.
• Studying the effects of COVID-19 on the heart.^[11]

Virology and immunology[]

In 1991, Gladstone expanded its focus to include virology and immunology, in response to the HIV/AIDS crisis. The institute has since focused on numerous diseases, including hepatitis C, Zika virus, and COVID-19.^[12] In 2011, Gladstone launched a $25 million initiative around HIV and aging.^[13]

Their research has included:

• Leading the global iPrEx study, which led to the FDA approval of Truvada for HIV prevention in 2012.^[14]
• Participating as a member of the Martin Delaney Collaboratory to study HIV latency.^[15]
• Studying the "accelerated aging" effects associated with HIV/AIDS.^[16]
• Studying how HIV integrates and replicates within the body, and how it kills lymphoid CD4 T-cells, the fundamental cause of AIDS.^{[17][18][19][20][21]}

In 2020, two new institutes were formed; the Gladstone Institute of Virology, and the Gladstone-UCSF Institute of Genomic Immunology, to study how viruses interact with human cells to cause disease.^[22]

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.^[23]
• 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.^[24]
• TDP-43. Studying TDP-43, another protein that may contribute to diverse neurodegenerative disorders.^[25]
• 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.^[26]
• 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.^[27]
• 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.^[28]
• 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.^[29]

Stem cell technology[]

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.^[30] In 2012 Yamanaka was awarded the Nobel Prize in Physiology or Medicine.^[31]

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:^[32]

• Reprogramming cardiac connective tissue located in the heart directly into beating cardiac muscle cells.^[33]
• Discovering new ways to use chemical compounds to convert cells from one type into another.^[34]
• Direct reprogramming of cells into neurons and neural precursor cells.^[35]
• 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 Advancement was formed in 2017, and focuses on drug repositioning; repurposing already-approved drugs for new uses and clinical trials, to speed up (and lower the cost of) drug development.^[36]

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.^[33]
• 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.^[37] 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.^[30]
• 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.^[28]
• 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.^[34]
• 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.^[26]
• 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.^[38][39] 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.^[40][41] Recently, pyroptosis and downstream pathways were identified as promising targets for treatment of severe coronavirus disease 2019–associated diseases.^[42]
• 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.^[35][43] 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.^[44][45][46]
• 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.^[23]
• Katherine Pollard
• R. Sanders Williams
• 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
• Leor Weinberger

References[]

External links[]

• Official site