Gladstone researchers study these diseases using techniques of basic and translational science. Another focus at Gladstone is building on the stem cell breakthrough of one of its investigators, 2012 Nobel Laureate Shinya Yamanaka, MD, PhD, to improve drug discovery, personalized medicine and tissue regeneration. .
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.
Gladstone Institutes research articles from Innovation Toronto
- Scientists Turn Skin Cells into Heart Cells and Brain Cells Using Drugs – April 29, 2016
- Combining the two most powerful biological tools of the 21st century to Control Gene Expression in Stem Cells – CRISPRi – March 11, 2016
- Gladstone scientists discover potential new treatment for multiple sclerosis – April 29, 2015
- Transplantation of healthy new brain cells reverses learning and memory loss in Alzheimer’s disease model – July 18, 2014
- Building the Tools that Fight Type 1 Diabetes
- New Breakthrough Prize Awards Millions to Life Scientists
- New hope for Alzheimer’s sufferers as breakthrough allows scientists to grow new brain cells from normal skin
- Scientist Converts Human Skin Cells Into Functional Brain Cells
A new way to regulate protein levels and functions could be the answer to treating devastating neurological conditions
New details learned about a key cellular protein could lead to treatments for neurodegenerative diseases, such as Parkinson’s, Huntington’s, Alzheimer’s, and amyotrophic lateral sclerosis (ALS).
At their root, these disorders are triggered by misbehaving proteins in the brain. The proteins misfold and accumulate in neurons, inflicting damage and eventually killing the cells. In a new study, researchers in the laboratory of Steven Finkbeiner, MD, PhD, at the Gladstone Institutes used a different protein, Nrf2, to restore levels of the disease-causing proteins to a normal, healthy range, thereby preventing cell death.
The researchers tested Nrf2 in two models of Parkinson’s disease: cells with mutations in the proteins LRRK2 and a-synuclein. By activating Nrf2, the researchers turned on several “house-cleaning” mechanisms in the cell to remove excess LRRK2 and ?-synuclein.
“Nrf2 coordinates a whole program of gene expression, but we didn’t know how important it was for regulating protein levels until now,” explained first author Gaia Skibinski, PhD, a staff research scientist at Gladstone. “Overexpressing Nrf2 in cellular models of Parkinson’s disease resulted in a huge effect. In fact, it protects cells against the disease better than anything else we’ve found.”
In the study, published in the Proceedings of the National Academy of Sciences, the scientists used both rat neurons and human neurons created from induced pluripotent stem cells. They then programmed the neurons to express Nrf2 and either mutant LRRK2 or a-synuclein. Using a one-of-a-kind robotic microscope developed by the Finkbeiner laboratory, the researchers tagged and tracked individual neurons over time to monitor their protein levels and overall health. They took thousands of images of the cells over the course of a week, measuring the development and demise of each one.
The scientists discovered that Nrf2 worked in different ways to help remove either mutant LRRK2 or ?-synuclein from the cells. For mutant LRRK2, Nrf2 drove the protein to gather into incidental clumps that can remain in the cell without damaging it. For a-synuclein, Nrf2 accelerated the breakdown and clearance of the protein, reducing its levels in the cell.
“I am very enthusiastic about this strategy for treating neurodegenerative diseases,” said Finkbeiner, a senior investigator at Gladstone and senior author on the paper. “We’ve tested Nrf2 in models of Huntington’s disease, Parkinson’s disease, and ALS, and it is the most protective thing we’ve ever found. Based on the magnitude and the breadth of the effect, we really want to understand Nrf2 and its role in protein regulation better.”
The scientists say that Nrf2 itself may be difficult to target with a drug because it is involved in so many cellular processes, so they are now focusing on some of its downstream effects. They hope to identify other players in the protein regulation pathway that interact with Nrf2 to improve cell health and that may be easier to drug.
Two chemicals improved the speed, quantity, and quality of direct cardiac reprogramming, bringing the technology one step closer to regenerating damaged hearts
Scientists at the Gladstone Institutes identified two chemicals that improve their ability to transform scar tissue in a heart into healthy, beating heart muscle. The new discovery advances efforts to find new and effective treatments for heart failure.
Heart failure afflicts 5.7 million Americans, costs the country $30.7 billion every year, and has no cures. When heart muscle is damaged, the body is unable to repair the dead or injured cells. Gladstone scientists are exploring cellular reprogramming–turning one type of adult cell into another–in the heart as a way to regenerate muscle cells in the hopes of treating, and ultimately curing, heart failure.
It takes only three transcription factors–proteins that turn genes on or off in a cell–to reprogram connective tissue cells into heart muscle cells in a mouse. After a heart attack, connective tissue forms scar tissue at the site of the injury, contributing to heart failure. The three factors, Gata4, Mef2c, and Tbx5 (GMT), work together to turn heart genes on in these cells and turn other genes off, effectively regenerating a damaged heart with its own cells. But the method is not foolproof–typically, only ten percent of cells fully convert from scar tissue to muscle.
In the new study, published in Circulation, Gladstone scientists tested 5500 chemicals to try to improve this process. They identified two chemicals that increased the number of heart cells created by eightfold. Moreover, the chemicals sped up the process of cell conversion, achieving in one week what used to take six to eight weeks.
“While our original process for direct cardiac reprogramming with GMT has been promising, it could be more efficient,” said senior author Deepak Srivastava, MD, director of the Gladstone Institute of Cardiovascular Disease. “With our screen, we discovered that chemically inhibiting two biological pathways active in embryonic formation improves the speed, quantity, and quality of the heart cells produced from our original process.”
The first chemical inhibits a growth factor that helps cells grow and divide and is important for repairing tissue after injury. The second chemical inhibits an important pathway that regulates heart development. By combining the two chemicals with GMT, the researchers successfully regenerated heart muscle and greatly improved heart function in mice that had suffered a heart attack.
The scientists also used the chemicals to improve direct cardiac reprogramming of human cells, which is a more complicated process that requires additional factors. The two chemicals enabled the researchers to simplify the process bringing them one step closer to better treatments for heart failure.
“Heart failure afflicts many people worldwide, and we still do not have an effective treatment for patients suffering from this disease,” said Tamer Mohamed, PhD, first author on the study and a former postdoctoral scholar at Gladstone. “With our enhanced method of direct cardiac reprogramming, we hope to combine gene therapy with drugs to create better treatments for patients suffering from this devastating disease.”
A biomaterials hack can boost cells’ ability to combat inflammation and potentially treat autoimmune diseases
With a trick of engineering, scientists at the Gladstone Institutes improved a potential weapon against inflammation and autoimmune disorders. Their work could one day benefit patients who suffer from inflammatory bowel disease or organ transplant rejection.
The Body’s Natural Defense
Mesenchymal stromal cells (MSCs) reside in bone marrow and have been found to secrete anti-inflammatory proteins that help regulate the immune system. More than 500 clinical trials are trying to use these cells to fight diseases, but so far, many have failed.
Scientists think this failure may be because, like a match needs to be sparked to create a flame, MSCs must be triggered by pro-inflammatory proteins to produce their immune-suppressing effects. Some studies have tried soaking MSCs in a bath of pro-inflammatory chemicals before injecting the cells into a patient. However, the effects are short-lived, wearing off after just a few days.
“The success of therapies involving MSCs depends on the cells’ environment,” explained Todd McDevitt, PhD, a senior investigator at Gladstone. “A patient taking anti-inflammatory medication may not have high enough levels of inflammation to trigger the cells. We engineered the MSCs to ensure that they are consistently activated, so they can reliably dampen the immune response for longer.”
Engineering A Better Method
In the new study, published in Stem Cells Translational Medicine, the scientists engineered tiny sugar-based particles that they loaded with pro-inflammatory proteins and stuck into the middle of clusters of MSCs. The particles slowly delivered the inflammatory trigger to the cells in a steady dose. This method increased the amount of anti-inflammatory proteins produced by the MSCs, enhancing the suppression of immune cells. In short, the cell-protein packets worked better and longer than other treatments.
“No one has successfully used biomaterials to deliver pro-inflammatory signals to control how MSCs affect the immune system,” said first author Josh Zimmermann, PhD, a former graduate student in the McDevitt lab. “Our research suggests bioengineering has real potential to improve the anti-inflammatory and therapeutic abilities of MSCs. The next step is to test this method in a mouse model of autoimmune disease.”
Learn more: How to Engineer a Stronger Immune System
Scientists at the Gladstone Institutes have invented a new way to create three-dimensional human heart tissue from stem cells. The tissue can be used to model disease and test drugs, and it opens the door for a precision medicine approach to treating heart disease. Although there are existing techniques to make three-dimensional tissues from heart cells, the new method dramatically reduces the number of cells needed, making it an easier, cheaper, and more efficient system.
“We have bioengineered micro-scale heart tissues with a method that can easily be reproduced, which will enable scientists in stem cell biology and the drug industry to study heart cells in their proper context,” said first author Nathaniel Huebsch, PhD, a postdoctoral fellow in the Conklin lab at Gladstone. “In turn, this will enhance our ability to discover treatments for heart disease.”
Creating heart cells from induced pluripotent stem cells (iPSCs) that are derived from a patient’s skin cells enables scientists to study and test drugs on that patient’s specific disease. However, cells made from iPSCs are relatively immature, resembling heart cells in an embryo more than cells in an adult. As such, these cells are inadequate for drug testing because they do not properly predict how a drug will affect adult heart cells. Additionally, heart cells created from iPSCs are challenging to make and work with, so creating large quantities can be difficult. Therefore, the fewer cells needed, the better.
The micro heart muscle addresses both of these concerns.
The new cells prevented the onset of diabetes in an animal model of the disease bringing personalized cell therapy for diabetes closer.
Scientists at the Gladstone Institutes and the University of California, San Francisco (UCSF) have successfully converted human skin cells into fully-functional pancreatic cells. The new cells produced insulin in response to changes in glucose levels, and, when transplanted into mice, the cells protected the animals from developing diabetes in a mouse model of the disease.
The new study, published in Nature Communications, also presents significant advancements in cellular reprogramming technology, which will allow scientists to efficiently scale up pancreatic cell production and manufacture trillions of the target cells in a step-wise, controlled manner. This accomplishment opens the door for disease modeling and drug screening and brings personalized cell therapy a step closer for patients with diabetes.