Black Family Stem Cell Institute

Pluripotent Stem Cells

Pluripotent stem cells can develop into any cell type in our body. Embryonic stem cells and cells reprogrammed or induced to the pluripotent cell state (iPSC) have this capacity.

Deriving iPSCs directly from the tissues of patients paves the way for personalized medicine by allowing us to study the individual's unique biology. We can now fashion in vitro models of healthy and diseased human tissues using stem cell-based protocols. For example, neuronal organoids reliably recapitulate the in vivo functions in the cell culture dish and undergo changes in structure and function stereotypic for neurodegenerative diseases. Although the models are incomplete in many ways, they often point us to entirely new aspects of disease processes and therefore attract exceptional interest across all disciplines. A recent review article listed more than 100 diseases that can be modeled using patient-derived induced pluripotent stem cells. Not only will this technology allow us to learn about new disease mechanisms and identify novel compounds for treatment, but it will also let us develop new diagnostic tools such as early biomarkers.

At the Black Family Stem Cell Institute, we are combining advances in pluripotent stem cell research and gene editing in powerful ways. For example, we use CRISPR to introduce into human iPSCs genetic mutations that cause disease and grow these mutated iPSCs into tissue organoids that exhibit disease-specific phenotypes. The ability to model an individual patient's particular disease—not just the disease-causing mutation itself but the patient's entire genomic and epigenetic landscape—is central to understanding how a patient will respond to a particular therapy. 

The potential for truly personalized medicine is astounding. Mount Sinai is taking advantage of the stem cell revolution to offer its patients the best treatments. Likewise, personalized medicine enables researchers to build on current strengths and set a solid foundation for future endeavors. Our faculty develop more authentic and specific disease models using stem cells or organoids for studying mechanisms and screening therapies in many diseases, including neurological disease, cancer, retinal disorders, and cardiovascular problems.

Investigators with a major focus in pluripotent stem cell biology and its uses in regenerative therapies and personalized medicine include:

Tim D. Ahfeldt, PhD

Tim Ahfeldt, PhD, is an Assistant Professor in the Nash Family Department of Neuroscience at the Icahn School of Medicine at Mount Sinai, the Ronald M. Loeb Center for Alzheimer’s disease, and The Friedman Brain Institute. Dr. Ahfeldt’s research asks why some cells are more vulnerable to neurodegenerative disease than others. Developing new tools to address this question will aid us in understanding pathological mechanisms and advancing pharmacological interventions. Human pluripotent stem cells (hPSCs), which can be differentiated into all cell types, provide an unparalleled system for studying human neurodegenerative diseases in vitro. For example, Parkinson’s disease (PD) is characterized by the almost complete loss of midbrain dopaminergic neurons in the substantia nigra pars compacta, while the closest relatives in the ventral tegmental area are relatively spared. Using CRISPR gene editing techniques, we have developed several isogenic hPSCs models of PD. Our data suggest that our PD model recapitulates disease aspects found in vivo as we observe selective vulnerability in differentiated midbrain dopaminergic neurons in PD lines, providing us with an opportunity to address the question of specific cell type vulnerability in a novel way.

Ongoing research interests include:

  • Determining how disease genotype impacts phenotype and affects specific cell-types
  • Identifying disease relevant common and unique pathways in order to uncover new therapeutic targets

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James J. Bieker, PhD

James J. Bieker, PhD, is a Professor in the Department of Cell, Developmental, and Regenerative Biology at the Icahn School of Medicine at Mount Sinai. The laboratory's interest is in the transcriptional regulation of red blood cell-specific gene expression, and in identifying the molecular events that confer the ability to express lineage-specific genes in uncommitted, pluripotent hematopoietic stem cells. These issues are being addressed by the functional analysis of a novel, erythroid-specific gene that the Bieker Laboratory identified a number of years ago named erythroid Krüppel-like factor; EKLF. Biochemical, molecular, cellular, developmental, and genetic studies in mice and humans have established that EKLF is an essential component required for globin switching and completion of the definitive erythroid program.

Using our model system, we aim to disentangle genotype from phenotype and cell-type and identify disease relevant common and unique pathways that hold promise for future therapies.

Ongoing research interests include:

  • Analyzing EKLF protein/protein interactions and how they result in altered transcriptional and epigenetic changes at target loci
  • Determining how molecular controls converge to regulate late events in erythropoiesis, particularly enucleation
  • Analyzing EKLF upstream regulators to explain its exquisite tissue-restricted expression pattern, and to possibly link alteration of its expression level to aberrant red cell biology
  • Determining the mechanism by which a human mutation in EKLF leads to congenital dyserythropoietic anemia.

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Timothy A. Blenkinsop, PhD

Timothy A. Blenkinsop, PhD, is an Assistant Professor in the Department of Cell, Development, and Regenerative Biology at the Icahn School of Medicine at Mount Sinai, as well as member of the Ophthalmology Department, the Black Family Stem Cell Institute, and Mount Sinai’s Eye and Vision Research Institute. His team is interested in understanding human retina development in normal and pathological situations, as well as in modeling in vitro various eye diseases. The lab’s primary interest lies in retina stem cell biology, cell replacement therapy, and endogenous retina regeneration potential. The lab uses adult human tissues and pluripotent stem cells-derived differentiated cells to probe retina physiology and model diseases such as age-related macular degeneration, proliferative vitreoretinopathy, and proliferative diabetic retinopathy. The main goal is to identify epigenetic regulation of cell plasticity for stimulating it with therapeutic benefit, while also modeling diseases where plasticity leads to disease.

Ongoing research interests include:

  • Exploring signaling transduction pathways involved in retinal pigment epithelium plasticity
  • Exploring cell replacement therapy for age-related macular degeneration
  • Researching cell fate specification of developing human eye field

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Kristen Brennand, PhD

Kristen Brennand, PhD, is an Associate Professor of Genetics and Genomics, Neuroscience, and Psychiatry at the Icahn School of Medicine at Mount Sinai. She trained in developmental and stem cell biology at Harvard University and in neuroscience during her postdoctoral studies at the Salk Institute for Biological Studies. By blending expertise in stem cell biology and neurobiology, she has pioneered a new approach to study psychiatric disease. By developing a G16 based model for the study of predisposition to neuropsychiatric disease, and combining it with CRISPR-based genomic engineering, the Brennand Laboratory has established a new approach by which to systematically test the impact of causal variants in human cells. The future of psychiatry requires a model of precision medicine, in which doctors consider how the patient’s genetic variants—and the many interactions among them—affect disease course and treatment response before prescribing any medication.

Ongoing research interests include:

  • Understanding the genetic mechanisms underlying schizophrenia
  • Developing personalized screening platforms to identify new therapeutics for the treatment of this debilitating disorder

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Joseph Castellano

Joseph Castellano, PhD is an Assistant Professor of Neuroscience and Neurology and member of the Friedman Brain Institute and the Ronald M. Loeb Center for Alzheimer’s disease at the Icahn School of Medicine at Mount Sinai. Understanding the mechanism by which aging acts as a major risk factor for neurodegenerative disorders is critical as the aging population increases in the coming decades. Recent work has demonstrated that age-related changes in neural cells of the neurogenic niche within hippocampus are regulated by cues present in the systemic environment. Research in the Castellano laboratory is focused on understanding the molecular mechanisms underlying such blood-CNS communication, as well as the extent to which this communication shapes development of brain neuropathology in neurodegenerative diseases. Towards the goal of developing novel therapies that exploit this putative communication, the laboratory is interested in identifying and defining youth-associated activities that can rescue aspects of Alzheimer’s-related pathology. The Castellano laboratory specializes in a wide range of genetic tools in mouse models to answer complex physiological and compartmental questions related to brain function. Multiple levels of analysis are incorporated in the laboratory’s experimental aims, including editing in cell culture, human disease modeling in mice via viral-mediated and cell transfer tools, and cognitive behavioral assays. A focused goal of the group is to characterize the mechanism by which novel blood-borne factors mediate changes in function in the hippocampus.

Ongoing research interests include:

  • Characterizing mechanism of action of blood-borne factors within hippocampus
  • Understanding the role of genetic risk factors in regulating blood-brain communication in the context of disease.
  • creation of novel humanized mouse models to understand neuroimmune function in the context of disease pathology.

Marion Dejosez, PhD

Marion Dejosez, PhD, is an Assistant Professor in the Department of Cell, Developmental, and Regenerative Biology at the Icahn School of Medicine at Mount Sinai. She serves as Associate Director for the Huffington Center for Cell-Based Research in Parkinson’s Disease. Dr. Dejosez obtained her master’s degree in genetics from the University of Cologne and her PhD in cancer biology from the University of Dusseldorf. She trained as a postdoctoral fellow at the Center for Gene and Cell Therapy at Baylor College of Medicine in stem cell biology. During this time she discovered Ronin, a novel factor essential for embryogenesis and ES cell pluripotency (Cell, 2008, G&D 2010). She became an Assistant Professor in the Department of Molecular and Human Genetics in 2008 and subsequently directed the Stem Cell Core Facility at Baylor. In collaboration with the Zwaka Laboratory. She identified genes that safeguard stem cell growth in mouse embryogenesis (Science, 2013). She joined the faculty of Mount Sinai in 2013 where her studies continued to focus on understanding the molecular mechanisms that underlie embryonic stem cell pluripotency, self-renewal, and differentiation, with special emphasis on hematopoiesis and neurogenesis. Her research seeks to identify pathways that contribute to stem cell identity, and to understand their importance in tissue homeostasis and disease.

Ongoing research interests include:

  • Exploring Ronin’s contribution to genome organization in stem cells and their derivatives
  • Investigating Ronin’s function in hematopoiesis
  • Understanding the molecular mechanisms that contribute to neurodegenerative, diseases including ataxia and Parkinson’s disease using brain organoid and mouse models

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Nicole C. Dubois, PhD

Nicole Dubois, PhD, received her PhD in Cell and Developmental Biology from the Swiss Institute for Experimental Cancer Research and the University of Lausanne with Andreas Trumpp, PhD. She did her postdoctoral training in the laboratory of Gordon Keller, PhD, at the University Health Network in Toronto with a focus on pluripotent stem cell biology and their differentiation to cardiovascular lineages. She is currently an Associate Professor in the Department of Cell, Developmental, and Regenerative Biology at the Icahn School of Medicine at Mount Sinai, the Black Family Stem Cell Institute, and the Mindich Child Health and Development Institute. Dr. Dubois' group studies early heart development and congenital heart disease using pluripotent stem cell differentiations and the mouse embryo as model systems.

Ongoing research interests include:

  • Understanding the molecular mechanisms of atrial-ventricular development
  • Exploring pluripotent stem cell differentiation to cardiovascular lineages
  • Looking at cardiac maturation and tissue engineering
  • Investigating long non-coding RNAs during cardiac development
  • Exploring cardiac toxicity of cancer drugs (LINCS project)

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Bruce D. Gelb, MD

Bruce Gelb, MD, is the Gogel Family Professor of Child Health and Development and Professor of Pediatrics and Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai, and he directs the Mindich Child Health and Development Institute. He is a co-leader of a National Heart, Lung, and Blood Institute-funded training program in molecular and cellular cardiology. Dr. Gelb’s research group studies the genetic causes of cardiovascular diseases of childhood, particularly focusing on congenital heart defects and inherited disorders of the Ras/microtubule-associated protein (MAP) kinase signal transduction pathway (called RASopathies). His group, working with the then Black Family Stem Cell Institute Director, Ihor Lemischka, PhD, generated the first human induced pluripotent stem cell (hiPSC) model of a cardiovascular trait (hypertrophic cardiomyopathy for Noonan syndrome with multiple lentigines).

Ongoing research interests include:

  • Understanding the pathogenesis of hypertrophic cardiomyopathy for RASopathies
  • Discovering novel therapies for hypertrophic cardiomyopathy for RASopathies
  • Understanding congenital heart defect pathogenesis due to histone modifier mutations

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Saghi Ghaffari, MD, PhD, is a Professor of Cell, Developmental, and Regenerative Biology and a member of The Tisch Cancer Institute. Her lab studies mechanisms that sustain blood forming stem and progenitor cells (HSPCs) throughout life and that are perturbed in disease. Her team is particularly interested in programs that maintain quiescence of blood-forming stem cells, a property that determines the potency and overall regenerative capacity of adult stem cells and that is lost with age. Quiescence is also a mechanism by which malignant stem cells resist therapy. To attain this goal, the Ghaffari Laboratory has been investigating metabolic and mitochondrial-related programs and organelle communications in young and aged HSPCs. The Ghaffari lab uses a variety of approaches, including various omics, super resolution imaging, and gene modulation technology combined with genetically modified mouse models and human cells to address these questions.

Ongoing research interests include:

  • Investigating mechanisms that control mitochondria-lysosome communication in normal mouse and human hematopoietic stem cells (HSCs) in aged HSCs and in leukemic stem cells
  • Exploring transcriptional and epigenetic programs that regulate organelle biogenesis in HSPCs and their alteration with age
  • Investigating metabolic and redox regulation of erythroid cell maturation and identifying mechanisms and components of mitochondria-nucleus communication during this process
  • Elucidating mechanisms of apoptosis in beta-thalassemia

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Samuele G. Marro

Samuele G. Marro, PhD, is an Assistant Professor in the Nash Family Department of Neuroscience and co-Director of the Stem Cell Engineering Core at the Icahn School of Medicine at Mount Sinai. His research team focuses on the regulation of synaptic plasticity and its dysfunction in Fragile X syndrome, the number one genetic cause of autism. To accomplish this, the group studies human neurons directly differentiated from pluripotent stem cells that are genetically modified using CRISPR/Cas9 tools. The institutional Stem Cell Engineering Core itself provides services and resources at a reduced cost to the Icahn School of Medicine community that include the derivation of iPS from patient blood samples; iPS differentiation into different cell types; and gene-editing to create or repair putative disease mutations.

      

Ongoing research interests include:

  • Investigating protein homeostasis in human neurons
  • Exploring epigenetic regulation of synaptic plasticity
  • Understanding and correcting the epigenetic silencing in Fragile X syndrome

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Sarah E. Millar

Sarah E. Millar, PhD, is Director of the Black Family Stem Cell Institute, and Lillian and Henry M. Stratton Professorial Chair in the Departments of Cell, Developmental, and Regenerative Biology, and Dermatology at the Icahn School of Medicine at Mount Sinai. Understanding the molecular and cellular mechanisms regulating the development, patterning, and postnatal renewal of the skin and ectodermal appendage organs such as hair follicles, teeth, and taste papillae, and identifying stem and progenitor cell populations in these organs, is critical for developing new therapies to accelerate wound healing, treat hair loss diseases, repair or replace diseased teeth, and ameliorate taste dysfunction. Research in the Millar Laboratory focuses on cell-cell signaling and epigenetic mechanisms that underlie these processes. In published research, researchers identified Wnt/beta-catenin signaling as a key pathway required for initiating the formation of ectodermal appendages from multipotent cells in mammalian embryos, and in controlling development and patterning of haired versus hairy skin. By analyzing genetic mouse models and tissues from human patients carrying mutations in the WNT10A gene, we showed that Wnt signaling plays a key role in regulating the functions of a wide variety of adult epithelial stem cells, as well as in controlling specialized differentiation programs in palmoplantar skin. We have also identified critical functions for epigenetic regulators including micro-RNAs and chromatin modifiers in skin development and regeneration.

Ongoing research interests include:

  • Investigating mechanisms that cause ectodermal dysplasia in patients with mutations in the WNT10A gene, and testing potential therapeutic strategies
  • Determining the mechanisms that underlie the formation and maintenance of hairy versus hairless skin and regulate hair patterning
  • Delineating the functions of histone deacetylase chromatin modifiers in skin development, stem cells, and cancer
  • Identifying pioneer transcription factors that control development and stem cell activity in skin and oral epithelia

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Kateri Moore, DVM

Kateri Moore, DVM, is a Professor in Cell, Developmental, and Regenerative Biology at the Icahn School of Medicine at Mount Sinai and a member of The Tisch Cancer Institute. Her research is focused on both normal and reprogrammed hematopoietic stem cells (HSCs). To study normal hematopoiesis, she uses mouse models that allow her to define the characteristics of temporally defined quiescent HSCs during homeostasis. She researches perturbed hematopoiesis and aging HSCs using this model. These studies have implications for understanding the ability of leukemic stem cells and other tumor initiating cells to mimic normal stem cells and remain quiescent, thus evading current therapies. Her lab has reported direct reprogramming of mouse and human fibroblasts into hematopoietic cells using transcription factors. Insights gained during the reprogramming studies have led to the prospective isolation of the immediate precursor cell that give rise to definitive HSC during embryonic development. These studies have broad applications to cancers of the blood and immune system and others that require a stem cell transplant.

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Eirini Papapetrou, MD, PhD

Eirini Papapetrou, MD, PhD, is an Associate Professor of Oncological Sciences, Hematology, and Medical Oncology at the Icahn School of Medicine at Mount Sinai; and Associate Director of the Pluripotent Stem Cell Engineering Core. Her laboratory pioneered the modeling of blood cancers with human-induced pluripotent stem cell (iPSC). Specifically, her lab developed the first iPSC models of myeloid malignancies, including myelodysplastic syndromes and acute myeloid leukemia by reprogramming patient cells and by correcting and introducing mutations using CRISPR/Cas9-mediated gene editing. Dr. Papapetrou’s research program combines techniques and principles from stem cell research, cancer biology, and hematopoiesis with the goal of understanding disease mechanisms and identifying new therapeutic targets for hematologic malignancies. The unifying theme of the lab’s projects is the creation of genetically precise isogenic iPSC models of myeloid cancers and exploitation of the unique capabilities they offer for genotype-to-phenotype studies, interrogation of the effects of oncogenic mutations with integrative genomics analyses in a faithful cellular and genomic environment and genetic (CRISPR), and small molecule screens for drug repurposing or drug discovery. Dr. Papapetrou is the recipient of several awards, including the American Society of Gene and Cell Therapy Outstanding New Investigator Award, Damon Runyon-Rachleff Innovation Award, American Society of Hematology Scholar Award, Pershing Square Sohn Prize, and Leukemia and Lymphoma Society Scholar award, among others. She is an elected member of the American Society for Clinical Investigation.

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Christoph Schaniel, PhD

Christoph Schaniel, PhD, is an Assistant Professor in the Department of Pharmacological Sciences, the Department of Cell, Developmental and Regenerative Biology, and a member of the Mount Sinai Institute for System Biomedicine. His research is centered on understanding the cellular and molecular nature of hematopoietic stem cells (HSCs) in health and disease. He helped develop a clinical ex vivo expansion and cryopreservation process of umbilical cord blood HSCs for allogenic stem cell transplantation in refractory hematological malignancies that is being evaluated in a clinical trial (in collaboration with Ronald Hoffman, MD, and Camelia Iancu-Rubin, PhD). Additionally, he is investigating the mechanism and clinical applicability of direct reprogramming of HSCs from somatic cells for cell replacement therapies (together with Kateri A. Moore, DVM). Other research focuses on the effect of valproic acid on normal vs. malignant HSCs, the underlying pathologies of hematological malignancies and cancers using human primary stem cells, and induced pluripotent stem cells (PSCs). He is also invested in various projects aimed at understanding the mechanisms of cardiovascular diseases and drug action, responses, and toxicity in individuals using induced PSCs with the goal of advancing and developing precise and personalized therapeutic treatments.

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Christopher M. Sturgeon

Christopher M. Sturgeon is an Associate Professor at the Icahn School of Medicine at Mount Sinai. Chris’s lab studies the development of the human hematopoietic system, using the in vitro differentiation of human pluripotent stem cells (hPSC) as a model system. The ability to differentiate hPSC towards a bona fide hematopoietic stem cell (HSC) would be a major step forward for the treatment of patients in need of a suitable donor match. Similarly, hPSCs offer unprecedented access to early embryonic hematopoietic lineages, which may have untapped clinical potential. To harness these possibilities, it is essential to be able to direct the differentiation of hPSCs in a controlled fashion. To that end, Chris’s research has developed defined media approaches, coupled with staged addition of recombinant morphogens such as BMP, WNT, and RA, to recapitulate these early embryonic developmental stages.

Ongoing research interests include:

  • Investigating the molecular mechanisms of hematopoietic development and the immediate precursor to the HSC, hemogenic endothelium
  • Characterizing the translational potential of HSC-independent immune lineages
  • Identifying the developmental trajectory of nascent mesoderm as it differentiates towards blood
  • Understanding the role of RNA splicing in embryonic hematopoiesis

Alexander M. Tsankov

Alexander M. Tsankov, PhD, is an Assistant Professor in Genetics and Genomic Sciences at Icahn School of Medicine at Mount Sinai. He completed his PhD in electrical engineering and computer science at MIT and his postdoctoral training at the Broad Institute and Harvard University (Alex Meissner and Aviv Regev’s lab). The Tsankov lab overall vision is to use genomics to build data-driven, predictive models that improve diagnosis, find new drug-able pathways, and personalize treatment of patients with lung cancer and respiratory diseases. The lab specializes in next generation sequencing (NGS) technologies (e.g. single-cell transcriptomic, epigenomic, and spatial data) and computational analysis with the goal of unraveling how the underlying regulatory mechanisms, cell-cell interactions, and regenerative lineages have changed in lung disease compared to normal lung tissue homeostasis.

Ongoing research interests include:

  • Using single-cell technologies to reconstruct the regenerative lineages in the human lung and to understand how these have been hijacked in cancer or altered in lung disease
  • Investigating cell-cell interactions and their role on lung regeneration, disease progression, and immunosuppression.
  • Dissecting the cell-type specific regulatory mechanisms underlying normal lung homeostasis and changes that arise in respiratory disease and lung cancer

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Nan Yang, PhD

Nan Yang, PhD, is an Assistant Professor of Neuroscience at the Icahn School of Medicine at Mount Sinai. She is also a member of The Friedman Brain Institute, and the Ronald M. Loeb Center for Alzheimer's Disease at Mount Sinai. She pioneered the work in direct lineage reprogramming from somatic cells to neural cells and its application in neuropsychiatric and neurological disease modeling. Her team studies how disease-associated risk variants contribute to pathogenesis of multiple neuropsychiatric disorders with a particular focus on understanding how patient mutations in chromatin modifying proteins and functional non-coding elements impact gene expression regulation and neuronal function and contribute to autism spectrum disorder (ASD).

 

Ongoing research interests include:

  • Modeling ASD mutations in chromatin factors by directed differentiation protocols of human pluripotent stem cells into neurons
  • Understanding the role of the epigenome and non-coding DNA elements in neuronal signaling dependent gene regulation in different human neuronal subtypes
  • Exploring the mechanisms underlying transcription factors directed differentiation of human stem cells to neuronal subtypes.
  • Investigating autophage in human neurons and assessing functional outcome of mutations in Alzheimer's disease and Parkinson’s disease that affect autophage pathways.

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Zwaka headshot

The Zwaka Lab’s main line of research investigates ways to direct pluripotent stem cells to replace human cells affected by injury or disease. Dr. Zwaka was recruited to Mount Sinai in 2013 to become Professor of Developmental and Regenerative Biology. After earning his MD and PhD degrees from Ulm University in Germany, Dr. Zwaka trained as a cardiologist and discovered the link between C-reactive protein and atherosclerotic inflammation, a connection that has had enormous importance for cardiology. Dr. Zwaka then went to the University of Wisconsin to do his postdoctoral fellowship in the lab of Jamie Thomson, who derived the first human embryonic stem cell line in 1998. In Thomson’s lab, Dr. Zwaka pioneered methods to genetically manipulate stem cells (gene editing). He then joined the faculty of Baylor College of Medicine, serving in both the Department of Molecular and Cellular Biology and in the Center for Cell and Gene Therapy. At Baylor, the Zwaka Lab discovered a key regulator of pluripotency that behaved so differently from canonical stem cell factors that it was named Ronin.

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