Areas of Investigation

Gladstone scientists are using stem cell science in our mission to better understand, prevent, treat and cure some of the world’s most relentless diseases.

Many of our investigators are building on the work of Shinya Yamanaka, MD, PhD. Currently a senior investigator at Gladstone, Dr. Yamanaka is the scientist who in 2006 discovered how to reprogram skin cells into stem cells that, like embryonic stem cells, can develop into virtually any other cell type in the body. This discovery of induced pluripotent stem cells, or iPS cells, has since fundamentally changed the fields of cell biology and stem cell research, opening promising new prospects for both personalized and regenerative medicine.

Since that time, scientists have made many advances in iPS technology and in cell-reprogramming methods that build on it. While all these advances show promise, it is still too early to say which approaches will yield the most effective results for human health. So, at Gladstone we continue to conduct research in several areas of stem cell biology.

For example, Deepak Srivastava, MD, is reprogramming cardiac connective tissue in the heart directly into beating cardiac-muscle cells. Warner C. Greene, MD, PhD, has been studying whether the retrotransposons (also known as jumping genes, because they move around within the chromosomes of a single cell) that reside in our DNA become more active when a skin cell is reprogrammed into an iPS cell. Shomyseh Sanjabi, PhD, is using iPS technology to create a new model for testing a vaccine for HIV/AIDS. Sheng Ding, PhD, is working on new ways to use chemical compounds to convert cells from one type into another—such as reprogramming skin cells directly into brain cells. And Steven Finkbeiner, MD, PhD, is using stem cell technology to create cell culture models of Huntington’s disease and Alzheimer’s disease.

Please click on the titles below to learn more about our work in iPS technology, direct reprogramming, chemical biology and areas of application.

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Pluripotent Stem Cells

In 2006, former Gladstone postdoctoral fellow Shinya Yamanaka, MD, PhD, developed a method for inducing skin cells from mice to become pluripotent stem cells. To do this, he treated skin cells with four factors (now called the Yamanaka factors) to induce them to revert back to their pluripotent state. He called them induced pluripotent stem cells, or iPS cells, and in the following year he used the same techniques for converting human skin cells into stem cells.

Such cells are called pluripotent because, like embryonic stem cells, they can develop into virtually any type of cell in the human body. These iPS cells are distinct from embryonic stem cells, though, because they are derived from adult tissue, rather than from embryos. Further, iPS cells are also different from adult stem cells, a small number of which naturally occur in the human body.

By culturing iPS cells in a dish and treating them with other factors, scientists later found a way to reprogram iPS cells into various cell types such as beating heart cells and neurons that transmit chemical signals. They have since used this technique for creating patient-specific cell lines that can be used to research everything from drug testing to regenerative medicine.

Dr. Yamanaka, who is now a senior investigator back at Gladstone, continues to improve iPS technology, making it more viable for regenerative purposes. Currently, he and his Gladstone lab are working on ways to better understand what exactly happens when iPS cells are created—and how to make the process more efficient for both regenerative and personalized medicine.

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Direct Reprogramming

As soon as Shinya Yamanaka, MD, PhD, showed how to turn back the clock on human cells—making induced pluripotent stem cells, or iPS cells, from adult skin cells—scientists around the world began to build on his technology. These iPS cells are pluripotent because, like embryonic stem cells, they can develop into virtually any type of cell in the human body.

One key stem cell advance over the past five years is called direct reprogramming. This technique can offer a host of advantages over iPS technology when adult cells are reprogrammed directly into another cell type—without first being instructed to revert back to the pluripotent state of stem cells. For example, direct programming can yield new cells more quickly and efficiently than other forms of iPS technology.

At Gladstone, Deepak Srivastava, MD, used direct reprogramming to transform the cardiac scar tissue that impairs heart function directly into beating cardiac-muscle cells. Sheng Ding, PhD, meanwhile, has reprogrammed skin cells directly into brain cells and cardiac cells without returning those cells to the pluripotent state, while Yadong Huang, MD, PhD, has reengineered skin cells into early-stage brain stem cells that are self-renewing and can develop into mature brain cells.

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Chemical Biology

Recent breakthroughs have revealed that there are different ways to transform adult cells into other cells types—be that pluripotent stem cells or specific cell types such as neurons.

Indeed, the original genetic factors used in iPS technology carry some risk of inducing cancer and other genetic problems (as does the use of embryonic stem cells) that chemical compounds may avoid. For example, Sheng Ding, PhD, has been working on ways to use pharmaceutical chemicals rather than genetic material to reprogram cells. Currently, he is screening a host of chemicals to identify which ones can: instruct stem cells to become a specific type of cell; or control the developmental state of certain cell types, such as cancer cells and immune cells. This breakthrough builds upon the work of Shinya Yamanaka, MD, PhD, who first transformed adult humans cells into pluripotent stem cells.

The use of pharmaceutical chemicals can also improve both the speed and efficiency of cellular reprogramming—effectively shortening the time it will take us to use stem cell technology as a tool for overcoming disease. Dr. Ding’s vision for that day features a heart patient whose new prescription medication causes scar tissue in her heart to transform into robust beating heart cells.

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Disease Application

Gladstone is a basic-research organization with a focus on three disease areas. All of our stem cell work is targeted at finding new ways to overcome cardiovascular, viral and neurological diseases.

The discovery of induced pluripotent stem cells, or iPS cells, has since fundamentally altered the fields of cell biology and stem cell research, opening promising new prospects for both personalized and regenerative medicine. In addition to providing an alternative option to the controversial use of embryonic stem cells, iPS cell technology also represents an entirely new platform for fundamental studies of human disease. Rather than using models made in yeast, flies or mice for disease research, iPS cell technology lets scientists create disease-research models built on cells from a patient with a specific disease. These iPS-based models contain a complete set of the genes that resulted in that disease—thus representing the potential for a far superior model for studying disease and testing disease therapies. In the future, for example, iPS cells could be used in a Petri dish to test both drug safety and efficacy for an individual patient.

Indeed, many drugs fail because they cause health problems that are not detected until clinical trials begin. Using iPS cell technology, researchers can develop heart cells, for example, from reengineered skin cells to test toxicity of drug therapies earlier in the drug-development process—reducing the failure risk for the ensuing and expensive animal or human trials.

At Gladstone, scientists are building on the work of Shinya Yamanaka, MD, PhD, who first developed iPS cell technology in 2006. They are researching the regenerative effects of iPS cells on animal models. For example, Deepak Srivastava, MD, who directs cardiovascular research at Gladstone, is working on ways to use iPS cell technology to re-grow heart muscle in individuals who have suffered heart attacks. Researchers are also testing whether iPS cell technology can help individuals with spinal cord injuries or those with neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease.