You have provided numerous key scientific contributions to stem cell research. Among many distinctions you are the founding director of the Center for Stem Cells and Regenerative Medicine at Sanford Burnham Prebys Medical Discovery Institute and you have served two terms as chair of the FDA’s Cellular, Tissue and Gene Therapy Advisory Committee. Can you briefly tell us how your interest in stem cells emerged and how this field can benefit the investigation of cell-cell communication? We will provide references for those that want more details.
I came to science from a route different from that followed by most people that work in biomedical research. During my early teenage years, I was already working with children that had behavioral problems and came from a disadvantaged backgrounds, and I considered a career as a child social worker. I noticed that these kids were very resilient, and many would rapidly improve if given enough support. As a college student, I kept looking for the mechanism of this resilience, and my interests became more molecular, going from studying the behavior of people to working with cells. When I entered medicine, it was natural for me to become a pediatrician. During my time in the newborn intensive care unit, I noticed that some babies had significant injuries of the brain at birth but somehow could later completely recover. In fact, I would sometimes see these same babies in my outpatient clinic a year later and one might not be able to tell that they even had a problem as a newborn. I found this astonishing, and my clinical professors told me that it was “what kids do”, but no one really understood the mechanism of this resilience.
After my MD/PhD, I was doing my postgraduate clinical training as well as my postdoctoral research training simultaneously. My project was to “build-a-brain-in-a-dish”, combining cells of different committed types. The main problem was that the cell types I isolated kept changing their identity while in culture; my lab head and colleagues told me that this was a “tissue culture artifact” and urged me to abandon the project. However, I thought that this phenomenon could help explain the resilience and plasticity of the nervous system I was trying to understand. I continued this project on my own without telling anyone, working on it at night during spare hours, until, after two years, I obtained a key result: undifferentiated immature brain cells from a single clone, transplanted into the brain of other mice, could give raise to many different mature cell types in different parts of the brain and would become the cell type appropriate to that part of the brain. These results were published in 1992 (Snyder et al, Cell 1992); this and other papers were able to show, for the first time, that there were stem cells in solid organs that could be harvested, expanded in a dish, and reimplanted, becoming normal parts of the brain’s cytoarchitecture. Until that time, stem cells had been known to exist only in the bone marrow and to give rise to blood cells. In neuroscience, people thought that the brain was absolutely static, that the cells you are born with are what you have forever, and when you lose them, they cannot be replaced. After our discovery of stem cells in the brain, along with some other kinds of observations by others, the nervous system came to be considered plastic and dynamic, even in into adulthood.
After these results, I focused my work on neural stem cells, and many papers followed that, at the same time, clarified the behavioral, capacity, “language”, role, and utility of these cells therapeutically, and helped provide insights and models for important prototypical neurological diseases, including diseases characterized by gene deficiencies and cell deficiencies (e.g., Snyder et al, Nature 1995; Yandava et al, PNAS 1999). As mentioned by Robert Langer in his interview, in a collaborative paper (Teng et al, PNAS 2002), we were able to show substantial recovery of function after a neural stem cell transplant in a model of spinal cord injury. More work on this model, however, revealed a surprising finding: the benefit was not due to the replacement of nerve cells by the transplant, but rather by a protective effect on the cells of the host (Ourednik et al, Nat Biotech 2002). We called this protection the “chaperone effect” in stem cell biology. Virtually every clinical trial using stem cells up until this point, with few exceptions, relies on stem cells protecting rather than replacing host cells.
As the stem cell field has matured, we have realized that clinical progress cannot be based on simply obtaining any kind of cell in any kind of state and throwing them in anywhere and anytime into the nervous system; true progress must rely on a deep understanding of the complex interactions among the stem cells and the host cells as well as an intimate knowledge of the actual cause and pathophysiology of the specific disease and even of the specific patient. These cells communicate using diffusible factors, cell-cell contacts, and even microvesicles or exosomes. Nature uses stem cells for organogenesis and also for maintaining homeostasis and balance throughout life in the face of even day-to-day perturbations, let alone massive insults.
When there is an injury in the brain, the stem cells respond to the signals by moving towards the location of the injury. This phenomenon is called “homing pathotropism” and has important medical implications, for example as a therapy for gliomas in which a migratory stem cell can deliver a therapeutic payload to precisely where it is needed regardless of where it has been implanted (Aboody et al, PNAS 2000). One of the signals that stem cells follow are the inflammatory cytokines that are generated by many injuries or degenerative processes (Imitola et al, PNAS, 2004); the stem cells actually have receptors to these inflammatory molecules. In a recent paper (Lee et al, PNAS 2020), we were able to modify a prototypical inflammatory chemokine, CXCL12, so that it now became a benign drug that could guide stem cells to where their therapeutic action was needed without creating a potentially damaging inflammatory effect. In fact, the stem cells were able to suppress inflammation (one the therapeutic action of stem cells that we discovered a number of years ago) (Park et al, Nat Biotech, 2002; Teng et al, Sci Transl Med, 2012; Lee et al, Nat. Med, 2007; Lee et al, PNAS, 2020).
Another important application of stem cells is as tools for studying the effects of drugs in vitro. This is an extension of my old aim of building a brain in a dish. We can generate models for normal and diseased organs, and use cells from an individual patient that can contribute to personalized therapy. We have learned from such models the molecular basis of some psychiatric and other cognitive and neurodegenerative disorders. We are building improved brain organoids that have all the cell layers of normal brains to try to understand diseases in the brains of newborns. Spearheaded by my present lab co-leader, Sandra Leibel (Leibel et al, Curr Protoc Stem Cell Biol 2020), we have developed mini lungs-in-a-dish that have been used to evaluate therapies against COVID-19, as well as to understand some of the fundamental pathobiology of SARS-CoV-2 and other viral infections, including unveiling a novel autonomous intrapulmonary inflammatory feedback loop.
More generally, what could we do to advance the understanding of cell-cell communication, and would this knowledge produce large medical benefits?
As the above-mentioned research on organoids shows, stem cells are important research tools that can be used to obtain 3-dimensional, multicellular avatars of an organ in vitro that we can scrutinize and manipulate easily in order to study cell-cell communication. In conjunction with modern techniques for gene editing, single cell analysis, imaging, and electrophysiology, we can not only gain insight into how an organ is put together, but also how it goes awry in disease states and how it might be returned to normal using drugs, molecules, or other cells. This is the next major tool in Regenerative Medicine. And this brings me full circle to what I started doing as a pediatric resident and fellow so many years ago – and which helped give birth the field of Regenerative Medicine.
Aboody, Karen S., Alice Brown, Nikolai G. Rainov, Kate A. Bower, Shaoxiong Liu, Wendy Yang, Juan E. Small, Ulrich Herrlinger, Vaclav Ourednik, Peter McL. Black, Xandra O. Breakefield, and Evan Y. Snyder "Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas." Proceedings of the National Academy of Sciences 97, no. 23 (2000): 12846-12851.
Imitola, J., Raddassi, K., Park, K.I., Mueller, F.J., Nieto, M., Teng, Y.D., Frenkel, D., Li, J., Sidman, R.L., Walsh, C.A., Snyder, E.Y. Khoury, S. J., 2004. Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1α/CXC chemokine receptor 4 pathway. Proceedings of the National Academy of Sciences, 101(52), pp.18117-18122.
Lee, J. P., Jeyakumar, M., Gonzalez, R., Takahashi, H., Lee, P. J., Baek, R. C., ..., Snyder, E. Y. Stem cells act through multiple mechanisms to benefit mice with neurodegenerative metabolic disease. Nature medicine, 13(4), (2007):439-447.
Lee, J.P., Zhang, R., Yan, M., Duggineni, S., Wakeman, D.R., Niles, W.L., Feng, Y., Chen, J., Hamblin, M.H., Han, E.B., Gonzalez, R., ..., Snyder, E. Y. "Chemical mutagenesis of a GPCR ligand: Detoxifying “inflammo-attraction” to direct therapeutic stem cell migration." Proceedings of the National Academy of Sciences 117, no. 49 (2020): 31177-31188.
Leibel, Sandra L., Rachael N. McVicar, Alicia M. Winquist, Walter D. Niles, and Evan Y. Snyder. "Generation of Complete Multi− Cell Type Lung Organoids from Human Embryonic and Patient‐Specific Induced Pluripotent Stem Cells for Infectious Disease Modeling and Therapeutics Validation." Current protocols in stem cell biology 54, no. 1 (2020): e118.
Ourednik, Jitka, Václav Ourednik, William P. Lynch, Melitta Schachner, and Evan Y. Snyder. "Neural stem cells display an inherent mechanism for rescuing dysfunctional neurons." Nature biotechnology 20, no. 11 (2002): 1103-1110.
Park, Kook In, Yang D. Teng, and Evan Y. Snyder. "The injured brain interacts reciprocally with neural stem cells supported by scaffolds to reconstitute lost tissue." Nature biotechnology 20, no. 11 (2002): 1111-1117.
Snyder, Evan Y., David L. Deitcher, Christopher Walsh, Susan Arnold-Aldea, Erika A. Hartwieg, and Constance L. Cepko. "Multipotent neural cell lines can engraft and participate in development of mouse cerebellum." Cell 68, no. 1 (1992): 33-51.
Snyder, Evan Y., Rosanne M. Taylor, and John H. Wolfe. "Neural progenitor cell engraftment corrects lysosomal storage throughout the MRS VII mouse brain." Nature 374, no. 6520 (1995): 367-370.
Teng, Y. D., Benn, S. C., Kalkanis, S. N., Shefner, J. M., Onario, R. C., Cheng, B., ... & Snyder, E. Y. Multimodal actions of neural stem cells in a mouse model of ALS: a meta-analysis. Science translational medicine, 4(165), (2012):165ra164-165ra164.
Teng, Yang D., Erin B. Lavik, Xianlu Qu, Kook I. Park, Jitka Ourednik, David Zurakowski, Robert Langer, and Evan Y. Snyder. "Functional recovery following traumatic spinal cord injury mediated by a unique polymer scaffold seeded with neural stem cells." Proceedings of the National Academy of Sciences 99, no. 5 (2002): 3024-3029.
Yandava, Booma D., Lori L. Billinghurst, and Evan Y. Snyder. "“Global” cell replacement is feasible via neural stem cell transplantation: evidence from the dysmyelinated shiverer mouse brain." Proceedings of the National Academy of Sciences 96, no. 12 (1999): 7029-7034.