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A Decade of Stem Cell Research: A Q&A with Paul Frenette, M.D.

Dr. Paul FrenetteEditors’ Note: 2018 marks the 10-year anniversary of Einstein’s Gottesman Institute for Stem Cell Research and Regenerative Medicine. We sat down with the director, Paul Frenette, M.D., to discuss recent advances in the field, his own research projects and his expectations for the coming decade.

The Gottesman Institute for Stem Cell Research and Regenerative Medicine was established in 2008.  Can you tell us about some of the key advances that have come out of the institute over the past decade?

One example is the progress we’ve made in studying blood stem cells. Some of our scientists are characterizing blood stem cell renewal; others are trying to understand the malignant blood stem cells that cause cancer—the leukemic stem cells—and trying to target them selectively. We think it would be a good approach to treating leukemia.  Still other members are working to define breast cancer stem-cell populations, neural stem cells in brain regeneration and disease, embryonic stem cell differentiation to cure cataract and retinal diseases, among other projects.

At the stem cell and regenerative medicine symposium held at Einstein last year, you said that “the newest developments in stem cell biology—particularly in epigenetics—may prove transformative in the field” with regard to treatments. Could you elaborate on the connection between stem cells and epigenetics and the sorts of treatments you’re envisioning?

Yes, one example is the discovery by Shinya Yamanaka who was awarded the 2012 Nobel Prize in Physiology or Medicine for showing that mature cells such as skin cells could be reprogrammed to become induced pluripotent stem (iPS) cells, which closely resemble embryonic stem cells. During the reprograming, the epigenetic makeup of the cell is erased and rebooted. It illustrates the power of epigenetics to determine cell fate. In addition, a lot of genes involved in the epigenetic regulation of cells are involved in cancer as well. So understanding and manipulating the epigenetics of cells will also, I think, be really important in cancer therapy.

Are any researchers in the Gottesman Institute working with iPS cells?

Yes. Several are differentiating iPS cells into liver cells or into liver progenitor cells, to understand and study metabolic liver diseases.  Other scientists are differentiating iPS cells into neurons, to better understand autism and other neuropsychiatric diseases and to potentially regenerate parts of the brain, which could be useful for treating strokes.  We also have investigators who are working in the eye. Some are differentiating iPS cells into lenses, which could potentially be used for treating cataracts. Others are using iPS cells to form mini-retinas, to be able to also look for therapies for diseases that involve the retina, such as macular degeneration.

There was intense excitement when iPS cells were first created. Many thought they would revolutionize medicine. What are some of the challenges of developing stem cell treatments that non-scientists may not know or understand?

One of the many difficulties in developing therapies using iPS cells is that the cells are embryonic by definition.  So it’s a big challenge to differentiate them from the embryonic stage to a mature, adult stage and then, when they’re transferred into people, make sure they engraft in the right place and function normally.

Another major obstacle is ensuring that the genome of iPS cells remains intact as you differentiate them into cells to use in therapy. Culturing iPS cells can lead to genomic instability that induces mutations, so you may end up with a cell that’s prone to developing into a cancer.  That’s a very important consideration for therapy.

And, of course, there are issues of rejection when iPS cell derived from one person are used to treat another individual. It’s a complex process, but there has been significant progress over the past few years.

What do you think is the most under-appreciated aspect of stem cell research?

One thing people don’t realize is that there are multiple types of stem cells.  When I tell non-scientists that I conduct stem cell research, most people have heard of embryonic stem cells and think, “That’s what stem cells are.” They don’t know that there are many, many types of stem cells including adult stem cells, which have important functions in the body and can be isolated and targeted for therapy. Having so many types of stem cells makes our work more complicated—each type has to be cultured in its own way, for example—but it makes things more fun as well.

You mentioned cancer stem cells earlier. Does Einstein have a particular strength in this field?

I think we do. For leukemia, we have Ulrich Steidl, Kira Gritsman, Amit Verma, Keisuke Ito and Britta Will.  My lab is also touching on this in our work using normal stem cells to study leukemia. In addition, Winfried Edelmann and Len Augenlicht are working on intestinal cancer stem cells, and breast cancer stem cells is a major focus of Wenjun Guo’s lab. So we have a pretty sizeable group studying stem cells and cancer.

What are some of the advances in your own stem cell research over the past eight years since you came to Einstein?

We’ve made good headway in understanding the microenvironment that supports stem cells in the bone marrow—a very complex environment consisting of multiple cell types.  We’ve identified the key role that neurons play in regulating the stem cell microenvironment, which has led us to explore the role of nerves in regulating cancer and, potentially, the cancer stem cells.

We’ve also discovered that nerve fibers are really important in regulating prostate cancer progression.  And we’ve investigated the leukemia microenvironment, to determine how cancer stem cells influence the microenvironment cells that surround them.  We recently reported that aging causes the loss of nerve fibers in the bone marrow—something we think promotes the aging of stem cells and could influence stem cells to become malignant.

A decade ago, several states set up major stem cell research funding programs, including a program in California and New York State Stem Cell Science, known as NYSTEM. Would you consider those programs a success?

Of course, and the success can be measured in many ways. Certainly, researchers in our stem cell institute here at Einstein have benefited from multiple NYSTEM grants. Such programs also help fund research for junior people before they can get NIH grants, for example, and they help attract and retain people in the state who are working on stem cell research. Particularly in California, and also in New York, the funding has focused on translational medicine—making sure that patients benefit from laboratory stem-cell discoveries by promoting new human clinical trials.

The funding has also led discoveries that have resulted in new patents. And it has triggered the creation of new biotech companies and created new jobs as well.  So in my mind, there’s no doubt that those stem-cell funding mechanisms have been successful, and I hope more funding will become available.

What do you envision for the next 10 years of stem cell research—at Einstein and beyond?

I don’t have a crystal ball but am certainly optimistic, judging by the progress already made. Think about the new technologies that have evolved over the past decade, including CRISPR and all the single-cell technologies developed even more recently. As we make more discoveries in the lab, eventually there’ll be more clinical trials, and then effective treatments that will have a big impact on patient care.  If every stem cell research center was able to have one discovery relevant to patients, imagine the impact we would have across the country and world—it would be fantastic.  So that’s what we have to work towards, I think, in the next 10 years. It’s doable.

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