Gladstone Institutes Explained

Gladstone Institutes
Established:	1979
President:	Deepak Srivastava
Faculty:	30
Staff:	450
Budget:	$80 million
Location:	1650 Owens St., San Francisco, CA
City:	San Francisco
State:	California
Country:	United States

Gladstone Institutes should not be confused with Gatestone Institute.

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 inaugural 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. Also in 2011, the independent and philanthropic Gladstone Foundation formed with the mission of expanding the financial resources for the institutes.

Organizational structure

Gladstone Institutes consists of five institutes:

• Institute of Cardiovascular Disease
• Institute of Virology
• Institute of Neurological Disease
• Institute of Data Science & Biotechnology
• Institute of Genomic Immunology

Gladstone is also home to eight centers for researchers from different institutes to collaborate. These centers focus on stem and iPS cell research, as well as neurodegenerative disease research and therapeutics.^[10]

Research programs

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 various methods to repair damaged hearts, including creating heart cells from skin samples and converting scar tissue into muscle.^[11]
• 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.^[12]

Virology and immunology

In 1991, Gladstone expanded its focus to include virology and immunology in response to the HIV/AIDS crisis. Since then the institute has also studied hepatitis C, Zika virus, and COVID-19.^[13] In 2011, Gladstone launched a $25 million initiative around HIV and aging.^[14]

Their research has included:

• Leading the global iPrEx study, which led to the FDA approval of Truvada for HIV prevention in 2012.^[15]
• Participating as a member of the Martin Delaney Collaboratory to study HIV latency.^[16]
• Studying the "accelerated aging" effects associated with HIV/AIDS.^[17]
• Studying how HIV integrates and replicates within the body, and how it kills lymphoid CD4 T-cells, the fundamental cause of AIDS.^{[18] [19] [20] [21] [22]}

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.^[23]

The Institute of Virology has been involved in research regarding the COVID-19 virus, including its long-term effects on the heart,^[24] and studying samples of SARS-CoV-2 variations appearing in California, and their resistances to the Moderna and Pfizer vaccines.^{[25] [26]}

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 linking 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.^[27]
• 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.
• Alzheimer's disease and tau. Understanding how lowering brain levels of the tau protein improves memory and other cognitive functions in mice genetically engineered to mimic Alzheimer's disease. ^[28]
• TDP-43. Studying TDP-43, another protein that may contribute to diverse neurodegenerative disorders.^[29]
• 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.^[30]
• Investigating the network of brain cells that controls movement, and how its dysfunction leads to the symptoms of Parkinson's disease.^[31]
• Mitochondria and synaptic dysfunction. Studying mitochondria, the energy-producing subunits of cells, and their role in multiple neurodegenerative conditions, including Alzheimer's, Parkinson's and ALS.
• researching how autophagy can help prevent the destruction of brain cells, and how the p75 neurotrophin receptor —a protein involved in the development of brain cells— plays unexpected roles in both Alzheimer's and Type 2 diabetes.^[32]
• 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. 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.^{[33] [34]}

Stem cell technology

Another focus at Gladstone is building on the development of induced pluripotent stem cell technology by one of its senior investigators, 2012 Nobel Laureate Shinya Yamanaka. In 2006, Yamanaka discovered the technology, by which ordinary differentiated adult cells (such as fibroblasts from skin) could 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.^[35] In 2012 Yamanaka was awarded the Nobel Prize in Physiology or Medicine.^[36]

Since Yamanaka's discovery, scientists at Gladstone have used iPS technology to research solutions for Huntington's disease and Alzheimer's disease, as well as create a new model for testing HIV/AIVD vaccines.^[37]

Other work at the Data Science & Biotechnology Institute include:

• Reprogramming cardiac connective tissue located in the heart directly into beating cardiac muscle cells.^[38]
• Discovering new ways to use chemical compounds to convert cells from one type into another.^{[39] [40]}
• Direct reprogramming of cells into neurons and neural precursor cells.
• 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.

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.^[41]

Researchers

Current researchers at the institute include:

• Katerina Akassoglou, PhD — Senior Investigator
• Benoit Bruneau, PhD — Director, Gladstone Institute of Cardiovascular Disease
• Bruce Conklin, MD — Senior Investigator
• Sheng Ding, PhD — Senior Investigator
• Jennifer Doudna, PhD — Senior Investigator. Awarded the 2020 Nobel Prize in Chemistry.
• Barbara Engelhardt, PhD — Senior Investigator
• Steve Finkbeiner, MD, PhD— Director, Center for Systems and Therapeutics
• Warner Greene, MD, PhD — Director, Center for HIV Cure Research^{[42] [43] [44]}
• Yadong Huang MD, PhD — Senior Investigator^{[45] [46] [47]}
• Nevan Krogan, PhD — Senior Investigator
• Robert W. Mahley, MD, PhD — President emeritus and Senior Investigator
• Alex Marson, MD, PhD — Director, Gladstone-UCSF Institute of Genomic Immunology
• Lennart Mucke, MD — Director, Gladstone Institute of Neurological Disease
• Melanie Ott, MD, PhD — Director, Gladstone Institute of Virology
• Katherine Pollard, PhD — Director, Gladstone Institute of Data Science and Biotechnology
• Deepak Srivastava, MD — President, Gladstone Institutes
• Leor Weinberger, PhD — Senior Investigator
• Shinya Yamanaka— MD, PhD — Senior Investigator. Awarded the 2012 Nobel Prize in Physiology or Medicine.^[48]

Former researchers:

• Anatol Kreitzer, PhD — Senior Investigator
• Todd McDevitt, PhD — Senior Investigator

External links

• Official site

Notes and References

1. Web site: Gladstone boosts funding, science and fame. Leuty. Ron. July 27, 2012. www.bizjournals.com. 2020-02-19.
2. Web site: Gladstone, Jesse Dylan collaborate as research institute rebrands . Ron . Leuty . July 24, 2012 . San Francisco Business Times . bizjournals.com . 2019-06-26.
3. Web site: Gladstone to announce new stem cell center. Allday. Erin. 2011-10-19. SFGate. 2020-02-19.
4. Web site: Profile: The J. David Gladstone institutes . San Francisco Business Times . October 27, 2022 . February 25, 2007 .
5. http://www.pnas.org/content/103/15/5641/
6. Web site: The Gladstone Story . The Gladstone Institutes . 27 November 2014 . dead . https://web.archive.org/web/20141211000500/http://gladstoneinstitutes.org/about-us/the-gladstone-trust/history . 11 December 2014 .
7. Web site: Boost for biotech in S.F. / Gladstone Institutes to open Mission Bay research center. Levy. Dan. 2004-09-10. SFGate. 2020-02-19.
8. Web site: Williams spins science into fundraising gold. Leuty. Ron. April 29, 2011. www.bizjournals.com. 2020-02-19.
9. Web site: January 15 . Sam Hawgood . New President at Gladstone Institutes . Office of the Chancellor . en.
10. Web site: Science Gladstone Institutes . gladstone.org . 26 October 2021.
11. Web site: Ashley . Dan . Didion . Tim . Gladstone Institutes researchers use genetic clues to identify possible drug for treating heart conditions . ABC7 San Francisco . 15 July 2021 . en . 29 January 2021.
12. Perez-Bermejo . Juan A. . Kang . Serah . Rockwood . Sarah J. . Simoneau . Camille R. . Joy . David A. . Silva . Ana C. . Ramadoss . Gokul N. . Flanigan . Will R. . Fozouni . Parinaz . Li . Huihui . Chen . Pei-Yi . Nakamura . Ken . Whitman . Jeffrey D. . Hanson . Paul J. . McManus . Bruce M. . Ott . Melanie . Conklin . Bruce R. . McDevitt . Todd C. . SARS-CoV-2 infection of human iPSC-derived cardiac cells reflects cytopathic features in hearts of patients with COVID-19 . Science Translational Medicine . 10.1126/scitranslmed.abf7872 . 21 April 2021. 13 . 590 . eabf7872 . 33723017 . 8128284 .
13. Web site: Fimrite . Peter . SF's Gladstone Institutes splits research work in battle against coronavirus, future diseases . San Francisco Chronicle . 4 August 2021 . 13 May 2020.
14. Web site: Leuty . Ron . Gladstone boosts funding, science and fame . San Francisco Business Times . 20 August 2021.
15. Web site: Drug Approval Package: Truvada (emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) NDA #021752Orig1s030 . www.accessdata.fda.gov . 4 August 2021.
16. Web site: Federal funds may help Gladstone to solve problem of HIV latency . News-Medical.net . 4 August 2021 . en . 12 July 2011.
17. Gladstone scientists discover how immune cells die during HIV infection; identify potential drug to block AIDS . December 18, 2013 . UCSF.edu . 4 August 2021 . en.
18. Web site: FDA panel backs drug to prevent HIV infection risk. CBS Evening News.
19. 10.1016/j.cell.2010.11.001 . Abortive HIV Infection Mediates CD4 T Cell Depletion and Inflammation in Human Lymphoid Tissue . 2010 . Doitsh . Gilad . Cavrois . Marielle . Lassen . Kara G. . Zepeda . Orlando . Yang . Zhiyuan . Santiago . Mario L. . Hebbeler . Andrew M. . Greene . Warner C. . Cell . 143 . 5 . 789–801 . 21111238 . 3026834 .
20. 26321639 . 10.1016/j.celrep.2015.08.011 . 4565731 . 12 . 10 . Cell-to-Cell Transmission of HIV-1 Is Required to Trigger Pyroptotic Death of Lymphoid-Tissue-Derived CD4 T Cells . 2015 . Cell Rep . 1555–63 . Galloway . NL . Doitsh . G . Monroe . KM . Yang . Z . Muñoz-Arias . I . Levy . DN . Greene . WC .
21. 10.1038/nature12940 . Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection . 2014 . Doitsh . Gilad . Galloway . Nicole L. K. . Geng . Xin . Yang . Zhiyuan . Monroe . Kathryn M. . Zepeda . Orlando . Hunt . Peter W. . Hatano . Hiroyu . Sowinski . Stefanie . Muñoz-Arias . Isa . Greene . Warner C. . Nature . 505 . 7484 . 509–514 . 24356306 . 4047036 . 2014Natur.505..509D .
22. 24356113 . 10.1126/science.1243640 . 3976200 . 343 . 6169 . IFI16 DNA sensor is required for death of lymphoid CD4 T cells abortively infected with HIV . January 2014 . Science . 428–32 . Monroe . KM . Yang . Z . Johnson . JR . 2014Sci...343..428M . etal.
23. Web site: Gladstone-UCSF Institute of Genomic Immunology . The Stem Cellar . 30 August 2021 . en.
24. Web site: Ashley. Dan. Didion. Tim. 2021-03-27. Bay Area researchers probe how coronavirus attacks the heart. 2021-09-08. ABC7 San Francisco. en.
25. 2021-06-24 . Transmission, infectivity, and neutralization of a spike L452R SARS-CoV-2 variant . Cell . en . 184 . 13. 3426–3437.e8 . 33991487 . 10.1016/j.cell.2021.04.025 . 0092-8674 . 8057738 . Deng . Xianding . Garcia-Knight . Miguel A. . Khalid . Mir M. . Servellita . Venice . Wang . Candace . Morris . Mary Kate . Sotomayor-González . Alicia . Glasner . Dustin R. . Reyes . Kevin R. . Gliwa . Amelia S. . Reddy . Nikitha P. . Sanchez San Martin . Claudia . Federman . Scot . Cheng . Jing . Balcerek . Joanna . Taylor . Jordan . Streithorst . Jessica A. . Miller . Steve . Sreekumar . Bharath . Chen . Pei-Yi . Schulze-Gahmen . Ursula . Taha . Taha Y. . Hayashi . Jennifer M. . Simoneau . Camille R. . Kumar . G. Renuka . McMahon . Sarah . Lidsky . Peter V. . Xiao . Yinghong . Hemarajata . Peera . Green . Nicole M. . 1 .
26. Web site: Pfizer, Moderna COVID-19 vaccines induce responses against 2 key variants, small study finds. 2021-10-07. FiercePharma. May 17, 2021 . en.
27. Web site: Gladstone researchers find epilepsy drug that may work for Alzheimer's patients . San Francisco Business Times . August 6, 2012 . October 27, 2022 . bizjournals.com . Ron . Leuty .
28. News: Studies tie abnormal protein build-up to dementia . The New York Times .
29. Gladstone scientists identify role of key protein in ALS and frontotemporal dementia. January 12, 2010 . October 27, 2022 .
30. Web site: Robotic microscope: a tinker's breakthrough / Neural disease researcher melds optics and computer software. 28 March 2005.
31. Web site: Latest News, Diets, Workouts, Healthy Recipes - MSN Health & Fitness. healthyliving.msn.com.
32. Web site: NIH-funded Researchers Show Possible Trigger for MS Nerve Damage . September 24, 2015 . October 27, 2022 .
33. Web site: Researchers Lasso TDP-43 With RNA Lariats . Alzheimer's Research Forum . 6 November 2012 . October 27, 2022 .
34. 23104007 . 2012 . Armakola . M. . Higgins . M. J. . Figley . M. D. . Barmada . S. J. . Scarborough . E. A. . Diaz . Z. . Fang . X. . Shorter . J. . Krogan . N. J. . Finkbeiner . S. . Farese Jr . R. V. . Gitler . A. D. . Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models . Nature Genetics . 44 . 12 . 1302–1309 . 10.1038/ng.2434 . 3510335 .
35. Profile of Shinya Yamanaka. Prashant. Nair. 12 June 2012. Proceedings of the National Academy of Sciences. 109. 24. 9223–9225. 10.1073/pnas.1121498109. 22619323. 3386100. 2012PNAS..109.9223N . free.
36. News: Gurdon and Yamanaka Win Nobel Prize for Stem Cell Research. Nicholas. Wade. The New York Times. 8 October 2012.
37. Web site: Gladstone Institute Release: Study Reveals A New Method To Address A Major Barrier To Eradicating HIV . BioSpace . 26 October 2021.
38. Web site: Reversing a heart attack: scientists reprogram scar tissue into working muscle . Scientific American . April 18, 2012 . Christie . Wilcox . October 27, 2022 .
39. Web site: Skin cells reprogrammed into brain cells . June 7, 2012 .
40. 10.1016/j.stem.2011.05.010 . The Nomenclature System Should be Sustainable, but Also Practical . 2011 . Higashi . Hiroyuki . Brüstle . Oliver . Daley . George Q. . Yamanaka . Shinya . Cell Stem Cell . 8 . 6 . 606–607 . 21624802 . free .
41. Web site: Future Alzheimer's Therapy: Scientists fix ApoE4 in human brain cells. 2021-07-08. Neuroscience from Technology Networks. en.
42. Web site: Scientists Discover How Key Immune Cells Die During HIV Infection and Identify Potential Drug to Block AIDS. UC San Francisco.
43. 26962940 . 10.1016/j.chom.2016.02.012 . 4835240 . 19 . 3 . Dissecting How CD4 T Cells Are Lost During HIV Infection . Cell Host Microbe . 280–91 . Doitsh . G. . Greene . WC . 2016 .
44. Yap. Jeremy K. Y.. Moriyama. Miyu. Iwasaki. Akiko. 2020-07-15. Inflammasomes and Pyroptosis as Therapeutic Targets for COVID-19. Journal of Immunology. 205. 2. 307–312. 10.4049/jimmunol.2000513. 1550-6606. 7343621. 32493814.
45. Web site: Reprogamming Cells Could Eliminate Dangers of Side Effects in Medicine, US News & World Report. U.S. News & World Report.
46. Web site: Researchers Fix Genetic Risk Factor of Alzheimer's in Human Brain Cells. 9 April 2018.
47. 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
48. Web site: The Nobel Prize in Physiology or Medicine 2012 . Nobelprize.org .