Wernig Laboratory

"Only those who attempt the absurd can achieve the impossible."
– Albert Einstein
Our lab is generally interested in the molecular mechanisms that determine cell fates

Recently, we have identified a pool of transcription factors that are sufficient to convert skin fibroblasts directly into functional neuronal cells that we termed induced neuronal (iN) cells. This was a surprising finding and indicated that direct lineage reprogramming may be applicable to many somatic cell types and many different directions. Indeed, following our work others have identified transcription factors that could induce cardiomyocytes, blood progenitors, and hepatocytes from fibroblasts.

We are now focussing on two major aspects of iN and iPS cell reprogramming:

(i) we are fascinated by the puzzle how a hand full of transcription factors can so efficiently reprogram the entire epigenome of a cell so that it changes identity. To that end we are applying genome-wide expression analysis, chromatin immunoprecipitation, protein biochemistry, proteomics and functional screens.

(ii) it is equally exciting to now use reprogramming methods as tools to study or treat certain diseases. iPS cells have the great advantage that they can easily be genetically manipulated rendering them ideal for treating monogenetic disorders when combined with cell transplantation-based therapies. In particular we are working on Dystrophic Epidermolysis Bullosa in collaboration with Stanford's Dermatology Department. An exciting application of iN cell technology will be to try modeling neurological diseases in vitro. We perform both mouse and human experiments hoping to identify quantifiable phenotypes correlated with genotype and in a second step evaluate whether this assay could be used to discover novel drugs improve the disease progression.

Wernig Lab Research

Overview

Our lab is interested in the molecular mechanisms that define neural lineage identity focusing on transcription factors and chromatin biology. We use cellular reprogramming to understand how neurons are induced, how they mature and maintain their identity. Reprogramming also allows us to generate a novel tool box to study human neuronal and glial cell biology which become powerful human disease models in combination with genetic engineering. We further seek to develop reprogramming & genetic engineering approaches towards stem cell-based therapies. Finally, we study microglia-neuron interactions with the ultimate goal to understand the brain's immune system in health and disease and to exploit microglia for therapeutic and regenerative purposes.

induced neuronal cell from fibroblast

Human neuronal cell disease modeling

Neurosychiatric diseases like autism and schizophrenia are highly complex brain disorders difficult to model in mice in part due to complex genetic etiology and sometimes affecting human-specific genes. We develop novel human cell models to investigate disease-relevant cell biological phenomena.

Generation of defined human neuronal cell types to study neuronal cell biology

We have and continue to develop protocols to generate specific types of neurons such as pure glutamatergic and pure GABAergic neurons from human pluripotent stem cells using transcription factors. In combination with genetic engineering or deriving iPS cells from patients, we then interrogate the cell biology of human neurons that carry disease-causing mutations. A particular focus is on synaptic function as shown in the figure on the right on Fragile X Syndrome neurons in collaboration with Lu Chen and Tom Südhof's laboratories.

Making neurons from blood

The ability to generate functional induced neuronal cells from distantly related somatic cell types is fascinating but also offers the opportunity to obtain neurons from a larger cohort of human subjects. In particular blood is readily available and we showed can be efficiently converted into functional neurons from young and aged donors.

Cell scan

Developing next generation cell therapies

The combination of reprogramming and gene editing is truly powerful as it provides exciting new possibilities to generate cells that can be transplanted and have disease modifying activity. We currently apply this approach to restore mono-genetic diseases, but our vision goes beyond simple regenerative medicine. We will be able to genetically engineer designer cells that functionally integrate into diseased tissue equipped with sensing and intelligent disease-response mechanisms.

Towards a Phase 1 clinical trial for the fatal skin disease Epidermolysis Bullosa

Dystrophic Epidermolysis Bullosa is a severe, blistering monogenetic skin disease caused by mutations in the gene coding for type VII collagen. We have developed a 1-step gene editing/iPS cell reprogramming method to rapidly generate patient iPS cells corrected for their disease-causing mutations in the Collagen7a1 gene. In collaboration with dermatologist Tony Oro we are developing a cell manufacturing process compatible with Good Manufacturing Procedures (GMP) to obtain FDA-approval for a first in man Phase I clinical trial with with a genetically engineered iPS cell product.

Exploiting glia cell transplantation to treat neurodegenerative disease

Both oligodendrocyte precursor cells as well as microglia can efficiently repopulate the brain. We are interested in exploiting the properties of these cells to develop novel cell therapies for the brain either to use the transplanted cells to restore function such as myelination, to alter the function of transplanted cells for therepeutic benefit, to use the cells as vehicles for therapeutic molecules, or ultimately to develop designer cells that are engineered with genetic synthetic biology circuits to sense and interfere with disease processes of the brain.

cell scan

Mechanisms of neural cell lineage identity

We are interested in the molecular mechanisms that define neuronal and glial cell identity. We found sets of transcription factors that can convert fibroblasts or lymphocytes into neurons and oligodendrocytes. These factors are also operational during normal development and are largely responsible to induce terminal lineages from progenitor cells.

"On target" pioneer factors and chromatin remodeling during neuronal induction

We found that Ascl1, one of our reprogramming factors, has a unique ability to access its physiological targets even in fibroblasts where these sites are in a closed chromatin configuration. We are fascinated by this "on target" pioneering property and are investigating how Ascl1 can access its target sites in an unfavorable chromatin environment and how it then remodels the chromatin at these sites to activate the neuronal transcriptional program.

Maintenance of neuronal identity

Once neurons are made, there ought to be also mechanisms that maintain neuronal identity. We stumbled upon a novel repressive mechanism: The neuronal-specific transcription factor Myt1l continuosly represses many non-neuronal programs in neurons leaving the neuronal program open to activate by other factors and thereby ensuring stable neuronal gene expression. Myt1l was also recently found to be mutated in autism and schizophrenia.

Mechanisms of neural cell lineage diagram

Microglia-neuron interactions in the healthy and diseased brain

Microglia, the brain's resident immune cells, are fascinating cells. They are derived from yolk sac progenitor cells early during development, are long-lived, and are not exchanged from bone marrow progenitor cells under physiological conditions. Microglia have been implicated in synaptic pruning, adult neurogenesis, and various brain diseases including Alzheimer's disease and Schizophrenia.

Developing an efficient microglia replacement system

We have developed a method to efficiently replace endogenous microglia from circulating cells without genetic manipulation. This does not happen physiologically but under certain conditions peripheral blood cells cross the blood-brain-barrier, migrate into the brain parenchyma and replace endogenous cells. We are investigating the cellular and molecular signals that enable circulating cells to invade the brain in order to further improve microglia replacement strategies.

The role of microglia in the normal and the diseased brain

Our ability to replace microglia provides us with a powerful tool to functionally perturb microglia function in normal and disease states. E.g. the microglial gene TREM2 is a strong Alzheimer's disease risk gene, but major questions about the neuro-immune interplay in the context of neurodegeneration and aging remain unsolved. Microglia replacement also provides an exciting prospect to develop novel cell therapies for a variety of brain diseases including enzyme deficiency syndromes, neurodegeneration, and brain tumors.

Wernig Lab Publications

Efficient generation of dopaminergic induced neuronal cells with midbrain characteristics

Ng YH, Chanda S, Janas JA, Yang N, Kokubu Y, Südhof TC, Wernig M.

The differentiation of pluripotent stem cells can be accomplished by sequential activation of signaling pathways or through transcription factor programming. Multistep differentiation imitates embryonic development to obtain authentic cell types, but it suffers from asynchronous differentiation with variable efficiency. Transcription factor programming induces synchronous and efficient differentiation with higher reproducibility but may not always yield authentic cell types. We systematically explored the generation of dopaminergic induced neuronal cells from mouse and human pluripotent stem cells. We found that the proneural factor Ascl1 in combination with mesencephalic factors Lmx1a and Nurr1 induce peripheral dopaminergic neurons. Co-delivery of additional midbrain transcription factors En1, FoxA2, and Pitx3 resulted in facile and robust generation of functional dopaminergic neurons of midbrain character. Our results suggest that more complex combinations of transcription factors may be needed for proper regional specification of induced neuronal cells generated by direct lineage induction.

Pubmed Link
2021
Efficient generation of dopaminergic induced neuronal cells with midbrain characteristics
Stem Cell Reports

Ng YH, Chanda S, Janas JA, Yang N, Kokubu Y, Südhof TC, Wernig M.

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The differentiation of pluripotent stem cells can be accomplished by sequential activation of signaling pathways or through transcription factor programming. Multistep differentiation imitates embryonic development to obtain authentic cell types, but it suffers from asynchronous differentiation with variable efficiency. Transcription factor programming induces synchronous and efficient differentiation with higher reproducibility but may not always yield authentic cell types. We systematically explored the generation of dopaminergic induced neuronal cells from mouse and human pluripotent stem cells. We found that the proneural factor Ascl1 in combination with mesencephalic factors Lmx1a and Nurr1 induce peripheral dopaminergic neurons. Co-delivery of additional midbrain transcription factors En1, FoxA2, and Pitx3 resulted in facile and robust generation of functional dopaminergic neurons of midbrain character. Our results suggest that more complex combinations of transcription factors may be needed for proper regional specification of induced neuronal cells generated by direct lineage induction.

Cross-platform validation of neurotransmitter release impairments in schizophrenia patient-derived NRXN1-mutant neurons

Pak C, Danko T, Mirabella VR, Wang J, Liu Y, Vangipuram M, Grieder S, Zhang X, Ward T, Huang YA, Jin K, Dexheimer P, Bardes E, Mitelpunkt A, Ma J, McLachlan M, Moore JC, Qu P, Purmann C, Dage JL, Swanson BJ, Urban AE, Aronow BJ, Pang ZP, Levinson DF, Wernig M, Südhof TC.

Heterozygous NRXN1 deletions constitute the most prevalent currently known single-gene mutation associated with schizophrenia, and additionally predispose to multiple other neurodevelopmental disorders. Engineered heterozygous NRXN1 deletions impaired neurotransmitter release in human neurons, suggesting a synaptic pathophysiological mechanism. Utilizing this observation for drug discovery, however, requires confidence in its robustness and validity. Here, we describe a multicenter effort to test the generality of this pivotal observation, using independent analyses at two laboratories of patient-derived and newly engineered human neurons with heterozygous NRXN1 deletions. Using neurons transdifferentiated from induced pluripotent stem cells that were derived from schizophrenia patients carrying heterozygous NRXN1 deletions, we observed the same synaptic impairment as in engineered NRXN1-deficient neurons. This impairment manifested as a large decrease in spontaneous synaptic events, in evoked synaptic responses, and in synaptic paired-pulse depression. Nrxn1-deficient mouse neurons generated from embryonic stem cells by the same method as human neurons did not exhibit impaired neurotransmitter release, suggesting a human-specific phenotype. Human NRXN1 deletions produced a reproducible increase in the levels of CASK, an intracellular NRXN1-binding protein, and were associated with characteristic gene-expression changes. Thus, heterozygous NRXN1 deletions robustly impair synaptic function in human neurons regardless of genetic background, enabling future drug discovery efforts.

Pubmed Link
2021
Cross-platform validation of neurotransmitter release impairments in schizophrenia patient-derived NRXN1-mutant neurons
Proc Natl Acad Sci U S A

Pak C, Danko T, Mirabella VR, Wang J, Liu Y, Vangipuram M, Grieder S, Zhang X, Ward T, Huang YA, Jin K, Dexheimer P, Bardes E, Mitelpunkt A, Ma J, McLachlan M, Moore JC, Qu P, Purmann C, Dage JL, Swanson BJ, Urban AE, Aronow BJ, Pang ZP, Levinson DF, Wernig M, Südhof TC.

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Heterozygous NRXN1 deletions constitute the most prevalent currently known single-gene mutation associated with schizophrenia, and additionally predispose to multiple other neurodevelopmental disorders. Engineered heterozygous NRXN1 deletions impaired neurotransmitter release in human neurons, suggesting a synaptic pathophysiological mechanism. Utilizing this observation for drug discovery, however, requires confidence in its robustness and validity. Here, we describe a multicenter effort to test the generality of this pivotal observation, using independent analyses at two laboratories of patient-derived and newly engineered human neurons with heterozygous NRXN1 deletions. Using neurons transdifferentiated from induced pluripotent stem cells that were derived from schizophrenia patients carrying heterozygous NRXN1 deletions, we observed the same synaptic impairment as in engineered NRXN1-deficient neurons. This impairment manifested as a large decrease in spontaneous synaptic events, in evoked synaptic responses, and in synaptic paired-pulse depression. Nrxn1-deficient mouse neurons generated from embryonic stem cells by the same method as human neurons did not exhibit impaired neurotransmitter release, suggesting a human-specific phenotype. Human NRXN1 deletions produced a reproducible increase in the levels of CASK, an intracellular NRXN1-binding protein, and were associated with characteristic gene-expression changes. Thus, heterozygous NRXN1 deletions robustly impair synaptic function in human neurons regardless of genetic background, enabling future drug discovery efforts.

Cell-type-specific profiling of human cellular models of fragile X syndrome reveal PI3K-dependent defects in translation and neurogenesis

Raj N, McEachin ZT, Harousseau W, Zhou Y, Zhang F, Merritt-Garza ME, Taliaferro JM, Kalinowska M, Marro SG, Hales CM, Berry-Kravis E, Wolf-Ochoa MW, Martinez-Cerdeño V, Wernig M, Chen L, Klann E, Warren ST, Jin P, Wen Z, Bassell GJ.

Transcriptional silencing of the FMR1 gene in fragile X syndrome (FXS) leads to the loss of the RNA-binding protein FMRP. In addition to regulating mRNA translation and protein synthesis, emerging evidence suggests that FMRP acts to coordinate proliferation and differentiation during early neural development. However, whether loss of FMRP-mediated translational control is related to impaired cell fate specification in the developing human brain remains unknown. Here, we use human patient induced pluripotent stem cell (iPSC)-derived neural progenitor cells and organoids to model neurogenesis in FXS. We developed a high-throughput, in vitro assay that allows for the simultaneous quantification of protein synthesis and proliferation within defined neural subpopulations. We demonstrate that abnormal protein synthesis in FXS is coupled to altered cellular decisions to favor proliferative over neurogenic cell fates during early development. Furthermore, pharmacologic inhibition of elevated phosphoinositide 3-kinase (PI3K) signaling corrects both excess protein synthesis and cell proliferation in a subset of patient neural cells.

Pubmed Link
2021
Cell-type-specific profiling of human cellular models of fragile X syndrome reveal PI3K-dependent defects in translation and neurogenesis
Cell Rep

Raj N, McEachin ZT, Harousseau W, Zhou Y, Zhang F, Merritt-Garza ME, Taliaferro JM, Kalinowska M, Marro SG, Hales CM, Berry-Kravis E, Wolf-Ochoa MW, Martinez-Cerdeño V, Wernig M, Chen L, Klann E, Warren ST, Jin P, Wen Z, Bassell GJ.

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Transcriptional silencing of the FMR1 gene in fragile X syndrome (FXS) leads to the loss of the RNA-binding protein FMRP. In addition to regulating mRNA translation and protein synthesis, emerging evidence suggests that FMRP acts to coordinate proliferation and differentiation during early neural development. However, whether loss of FMRP-mediated translational control is related to impaired cell fate specification in the developing human brain remains unknown. Here, we use human patient induced pluripotent stem cell (iPSC)-derived neural progenitor cells and organoids to model neurogenesis in FXS. We developed a high-throughput, in vitro assay that allows for the simultaneous quantification of protein synthesis and proliferation within defined neural subpopulations. We demonstrate that abnormal protein synthesis in FXS is coupled to altered cellular decisions to favor proliferative over neurogenic cell fates during early development. Furthermore, pharmacologic inhibition of elevated phosphoinositide 3-kinase (PI3K) signaling corrects both excess protein synthesis and cell proliferation in a subset of patient neural cells.

H3.3-K27M drives neural stem cell-specific gliomagenesis in a human iPSC-derived model.
Haag D, Mack N, Benites Goncalves da Silva P, Statz B, Clark J, Tanabe K, Sharma T, Jäger N, Jones DTW, Kawauchi D, Wernig M, Pfister SM
Diffuse intrinsic pontine glioma (DIPG) is an aggressive childhood tumor of the brainstem with currently no curative treatment available. The vast majority of DIPGs carry a histone H3 mutation leading to a lysine 27-to-methionine exchange (H3K27M). We engineered human induced pluripotent stem cells (iPSCs) to carry an inducible H3.3-K27M allele in the endogenous locus and studied the effects of the mutation in different disease-relevant neural cell types. H3.3-K27M upregulated bivalent promoter-associated developmental genes, producing diverse outcomes in different cell types. While being fatal for iPSCs, H3.3-K27M increased proliferation in neural stem cells (NSCs) and to a lesser extent in oligodendrocyte progenitor cells (OPCs). Only NSCs gave rise to tumors upon induction of H3.3-K27M and TP53 inactivation in an orthotopic xenograft model recapitulating human DIPGs. In NSCs, H3.3-K27M leads to maintained expression of stemness and proliferative genes and a premature activation of OPC programs that together may cause tumor initiation.
Pubmed Link
2021
H3.3-K27M drives neural stem cell-specific gliomagenesis in a human iPSC-derived model.
Cancer Cell
Haag D, Mack N, Benites Goncalves da Silva P, Statz B, Clark J, Tanabe K, Sharma T, Jäger N, Jones DTW, Kawauchi D, Wernig M, Pfister SM
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Diffuse intrinsic pontine glioma (DIPG) is an aggressive childhood tumor of the brainstem with currently no curative treatment available. The vast majority of DIPGs carry a histone H3 mutation leading to a lysine 27-to-methionine exchange (H3K27M). We engineered human induced pluripotent stem cells (iPSCs) to carry an inducible H3.3-K27M allele in the endogenous locus and studied the effects of the mutation in different disease-relevant neural cell types. H3.3-K27M upregulated bivalent promoter-associated developmental genes, producing diverse outcomes in different cell types. While being fatal for iPSCs, H3.3-K27M increased proliferation in neural stem cells (NSCs) and to a lesser extent in oligodendrocyte progenitor cells (OPCs). Only NSCs gave rise to tumors upon induction of H3.3-K27M and TP53 inactivation in an orthotopic xenograft model recapitulating human DIPGs. In NSCs, H3.3-K27M leads to maintained expression of stemness and proliferative genes and a premature activation of OPC programs that together may cause tumor initiation.
Comparison of Acute Effects of Neurotoxic Compounds on Network Activity in Human and Rodent Neural Cultures.
Saavedra L, Wallace K, Freudenrich T, Mall M, Mundy W, Davila J, Shafer T, Wernig M, Haag D
Assessment of neuroactive effects of chemicals in cell-based assays remains challenging as complex functional tissue is required for biologically relevant readouts. Recent in vitro models using rodent primary neural cultures grown on multielectrode arrays (MEAs) allow quantitative measurements of neural network activity suitable for neurotoxicity screening. However, robust systems for testing effects on network function in human neural models are still lacking. The increasing number of differentiation protocols for generating neurons from human induced pluripotent stem cells (hiPSCs) holds great potential to overcome the unavailability of human primary tissue and expedite cell-based assays. Yet, the variability in neuronal activity, prolonged ontogeny and rather immature stage of most neuronal cells derived by standard differentiation techniques greatly limit their utility for screening neurotoxic effects on human neural networks. Here, we used excitatory and inhibitory neurons, separately generated by direct reprogramming from hiPSCs, together with primary human astrocytes to establish highly functional cultures with defined cell ratios. Such neuron/glia co-cultures exhibited pronounced neuronal activity and robust formation of synchronized network activity on MEAs, albeit with noticeable delay compared to primary rat cortical cultures. We further investigated acute changes of network activity in human neuron/glia co-cultures and rat primary cortical cultures in response to compounds with known adverse neuroactive effects, including GABAA receptor antagonists and multiple pesticides. Importantly, we observed largely corresponding concentration-dependent effects on multiple neural network activity metrics using both neural culture types. These results demonstrate the utility of directly converted neuronal cells from hiPSCs for functional neurotoxicity screening of environmental chemicals.
Pubmed Link
2021
Comparison of Acute Effects of Neurotoxic Compounds on Network Activity in Human and Rodent Neural Cultures.
Toxicol Sci
Saavedra L, Wallace K, Freudenrich T, Mall M, Mundy W, Davila J, Shafer T, Wernig M, Haag D
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Assessment of neuroactive effects of chemicals in cell-based assays remains challenging as complex functional tissue is required for biologically relevant readouts. Recent in vitro models using rodent primary neural cultures grown on multielectrode arrays (MEAs) allow quantitative measurements of neural network activity suitable for neurotoxicity screening. However, robust systems for testing effects on network function in human neural models are still lacking. The increasing number of differentiation protocols for generating neurons from human induced pluripotent stem cells (hiPSCs) holds great potential to overcome the unavailability of human primary tissue and expedite cell-based assays. Yet, the variability in neuronal activity, prolonged ontogeny and rather immature stage of most neuronal cells derived by standard differentiation techniques greatly limit their utility for screening neurotoxic effects on human neural networks. Here, we used excitatory and inhibitory neurons, separately generated by direct reprogramming from hiPSCs, together with primary human astrocytes to establish highly functional cultures with defined cell ratios. Such neuron/glia co-cultures exhibited pronounced neuronal activity and robust formation of synchronized network activity on MEAs, albeit with noticeable delay compared to primary rat cortical cultures. We further investigated acute changes of network activity in human neuron/glia co-cultures and rat primary cortical cultures in response to compounds with known adverse neuroactive effects, including GABAA receptor antagonists and multiple pesticides. Importantly, we observed largely corresponding concentration-dependent effects on multiple neural network activity metrics using both neural culture types. These results demonstrate the utility of directly converted neuronal cells from hiPSCs for functional neurotoxicity screening of environmental chemicals.
Optogenetic manipulation of cellular communication using engineered myosin motors.

Zijian Zhang, Nicolas Denans, Yingfei Liu, Olena Zhulyn, Hannah D Rosenblatt, Marius Wernig, Maria Barna

Cells achieve highly efficient and accurate communication through cellular projections such as neurites and filopodia, yet there is a lack of genetically encoded tools that can selectively manipulate their composition and dynamics. Here, we present a versatile optogenetic toolbox of artificial multi-headed myosin motors that can move bidirectionally within long cellular extensions and allow for the selective transport of GFP-tagged cargo with light. Utilizing these engineered motors, we could transport bulky transmembrane receptors and organelles as well as actin remodellers to control the dynamics of both filopodia and neurites. Using an optimized in vivo imaging scheme, we further demonstrate that, upon limb amputation in axolotls, a complex array of filopodial extensions is formed. We selectively modulated these filopodial extensions and showed that they re-establish a Sonic Hedgehog signalling gradient during regeneration. Considering the ubiquitous existence of actin-based extensions, this toolbox shows the potential to manipulate cellular communication with unprecedented accuracy.

Pubmed Link
2021
Optogenetic manipulation of cellular communication using engineered myosin motors.
Nat Cell Biol

Zijian Zhang, Nicolas Denans, Yingfei Liu, Olena Zhulyn, Hannah D Rosenblatt, Marius Wernig, Maria Barna

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Cells achieve highly efficient and accurate communication through cellular projections such as neurites and filopodia, yet there is a lack of genetically encoded tools that can selectively manipulate their composition and dynamics. Here, we present a versatile optogenetic toolbox of artificial multi-headed myosin motors that can move bidirectionally within long cellular extensions and allow for the selective transport of GFP-tagged cargo with light. Utilizing these engineered motors, we could transport bulky transmembrane receptors and organelles as well as actin remodellers to control the dynamics of both filopodia and neurites. Using an optimized in vivo imaging scheme, we further demonstrate that, upon limb amputation in axolotls, a complex array of filopodial extensions is formed. We selectively modulated these filopodial extensions and showed that they re-establish a Sonic Hedgehog signalling gradient during regeneration. Considering the ubiquitous existence of actin-based extensions, this toolbox shows the potential to manipulate cellular communication with unprecedented accuracy.

Marius Wernig

M.D., Ph.D.

wernig@stanford.edu


Dr. Marius Wernig is a Professor of Pathology and a Co-Director of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University. He graduated with an M.D. Ph.D. from the Technical University of Munich where he trained in developmental genetics in the lab of Rudi Balling. After completing his residency in Neuropathology and General Pathology at the University of Bonn, he then became a postdoctoral fellow in the lab of Dr. Rudolf Jaenisch at the Whitehead Institute for Biomedical Research/ MIT in Cambridge, MA. In 2008, Dr. Wernig joined the faculty of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University where he has been ever since.

He received an NIH Pathway to Independence Award, the Cozzarelli Prize for Outstanding Scientific Excellence from the National Academy of Sciences U.S.A., the Outstanding Investigator Award from the International Society for Stem Cell Research, the New York Stem Cell Foundation Robertson Stem Cell Prize, the Ogawa-Yamanaka Stem Cell Prize delivered by the Gladstone Institute and more recently has been named a Faculty Scholar by the Howard Hughes Medical Institute.

Dr. Wernig’s lab is interested in pluripotent stem cell biology and the molecular determinants of neural cell fate decisions. His laboratory was the first to generate functional neuronal cells reprogrammed directly from skin fibroblasts, which he termed induced neuronal (iN) cells. The lab is now working on identifying the molecular mechanisms underlying induced lineage fate changes, the phenotypic consequences of disease-causing mutations in human neurons and other neural lineages as well as the development of novel therapeutic gene targeting and cell transplantation-based strategies for a variety of monogenetic diseases.

Academic appointments

Associate Professor Institute for Stem Cell Biology and Regenerative Medicine


Member:
Bio-X
Cardiovascular Institute
Child Health Research Institute
Institute for Stem Cell Biology and Regenerative Medicine
Stanford Cancer Institute
Stanford Neurosciences Institute

Administrative appointments

Faculty Senate, Department of Pathology (2017 - Present)
Assistant Professor, Institute for Stem Cell Biology and Regenerative Medicine (2008 - 2014)

Honors & Awards

HHMI Faculty Scholar Award, Howard Hughes Medical Institute (2016)
New York Stem Cell Foundation Robertson Stem Cell Prize, New York Stem Cell Foundation (2014)
The Outstanding Young Investigator Award, International Society for Stem Cell Research (2013)
Ascina Award, Republic of Austria (2010)
Cozzarelli Prize for Outstanding Scientific Excellence, National Academy of Sciences USA (2009)
New Scholar in Aging, Ellison Medical Foundation (2010)
Robertson Investigator Award, New York Stem Cell Foundation (2010)
Donald E. and Delia B. Baxter Faculty Scholarship, Stanford University (2009)
Margaret and Herman Sokol Award, Biomedical Research (2007)
Longterm fellowship Human Frontiers Science Program Organisation, HFSP (2004-2006)

Boards, Advisory Committees

Professional Organizations Member, Society for Neuroscience (2003 - Present)
Member, International Society for Stem Cell Research (2004 - Present)
Editorial Board Member, Cell Stem Cell (2012 - Present)
Editorial Board Member, Stem Cell Reports (2013 - Present)
Member, Program Committee, Society for Neuroscience (2016 - Present)
Chair, Program Committee, International Society for Stem Cell Research (2017 - Present)

Professional Education

M.D., Technical University of Munich, Medicine (2000)

Wernig Lab Team

2020
2020
Bahareh Haddad Derafshi
PhD Student
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My current research interests are focused on epigenetic regulation of cognition at the level of synapses, using iN system. In my free time I do sports and outdoor activities, cook healthy food, make mixed drinks, play music, and collect vinyl records.

Bo Zhou
Postdoc Fellow
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I am studying synaptogenesis in Alzheimer’s Disease using human iNs as a model.

Danwei Wu
Neurology Resident Fellow
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Danwei Wu is a Stanford neurology resident in the Neuroscience Scholar Track and aspiring neuroimmunologist. Prior to starting residency, she completed an HHMI Medical Research Fellowship with Dr. Vann Bennett at Duke University studying neuron-specific membrane domains and their interaction with cytoskeletal structures. Her current research interest includes cell-based therapies for multiple sclerosis, molecular pathways of neuro-repair, and pathogenesis of autoimmunity. She is interested in developing new therapies for neurologic diseases.  Outside of the lab, she enjoys hiking and reading science fiction.

Gernot Neumayer
Postdoc Fellow
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I am a passionate cellular and molecular biologistwith expertise in research related to cancer, genomic/chromosomal instability, DNA damage response, epigenetics,  proteomics and cellular identity. The latter topic attracted me to the Wernig lab where I aim to decipher the mechanisms that allow us to specifically switch the identity of a cell, converting differentiated somatic cells into induced neurons. I also work on a project that aims to integrate CRISPR/CAS9-mediated gene correction with iPS cell generation in order to establish a therapy for the devastating skin disease epidermolysis bullosa. In my free time I play underwater rugby, surf, spearfish and ski!

Ishan Kumar
PhD Student
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I am a first-year PhD student interested in chromatin biology, cellular identity, and their practical applications. I am concurrently a third-year student at Stanford Law School, and previously attended Yale for my undergraduate studies.

Jacklyn Ha Luu
Undergrad
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I am an undergraduate studying neurobiology and computer science. In the Wernig Lab, I am studying how the interactions between reprogramming factors and chromatin modifiers allow for fully developed fibrojacklynl@stanford.edublasts to reprogram into induced neuronal cells (iN).

Jinzhao Wang
Joint Postdoc Fellow
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My research interests center around the application of patch clamp and calciumimaging methods on characterizing the phenotype of human-induced neuronal cells with neurological diseases-related mutations.

Justyna Janas
Postdoc Fellow
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I studied small GTPase signaling and how its perturbation can contribute to cancer and neurological disorders during my PhD training at Cold Spring Harbor Laboratory. Since then, I have become increasingly fascinated by the epigenetic mechanisms of gene regulation, and how changes in epigenome influence cell function and fate decisions. In the Wernig lab, I am currently investigating the interactions between the reprogramming factors and chromatin modifiers. More specifically, I am interested in finding out how such interactions enable a terminally differentiated cell—for example, a fibroblast—to acquire new transcriptional program that allows its reprogramming into induced neuron (iN).

Katie Schaukowitch
Postdoc Fellow
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My research interests include studying the molecular mechanisms underlying the establishment of neuronal identity and understanding how reprogramming factors can convert various cell types into neurons despite different epigenetic contexts.

Madhuri Vangipuram
Life science research professional
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The immense potential of genetic engineering technology as a tool to understand disease mechanisms and as a therapy motivates me to pursue research. I am studying CRISPR/Cas9 mediated gene correction of mutations in patients suffering from Epidermolysis bullosa. I am also studying iPSC-derived induced neurons to model neurological disorders.

Marius Mader
Postdoc Fellow
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As a neurosurgical resident, my research interests include translational topics such as cell therapy and neuroregenerative mechanisms. In the Wernig lab, I study the cellular reprogramming potential of microglia. Moreover, I’m interested in the functional integration of induced neurons into neural systems.

Takeshi Uenaka
Postdoc Fellow
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I worked as a neurologist for 10 years in Japan. During clinical practice, I saw a lot of patients who could not be treated by the current medicine. As a result, I became strongly attracted to basic research of neuroscience. I received my PhD in Dr. Tatsushi Toda’s lab at Kobe University, where I studied disease-modifying drug for Parkinson’s disease. As a post doc fellow in the Wernig lab, I’m interested in investigating the ubiquitylation enzymes that are associated with the pathophysiology of Alzheimer’s disease in order to cure patients with neurodegenerative diseases in the future. In my free time, I play with my children, go cycling, and read comics.

Tamara Chan
PhD Student
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I am a PhD student in the Department of Neurosciences and I joined the Wernig lab in the summer of 2020. I hope to study the fundamental cell biology of microglia giving rise to stable tiling in the brain. Furthermore, I am interested in how these mechanisms contribute to brain homeostasis and change with neuronal disease.

Tamas Danko
Basic Life Res Scientist
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My research interest is to investigate how genetic background contributes to the pathomechanism of complex mental disorders such autism or schizophrenia. In order to achieve my goals I am using various experimental techniques including rodent and human neuronal cell culture  preparations, immunohistochemistry, gene and protein expression analysis and electrophysiology. As a scientist, my motto is: "We work in the dark to serve the light. "

Wendy Fong
Postdoc Fellow
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Wendy received her Ph.D. from Columbia University, where she studied how cholesterol-rich membrane microdomains regulate a distinct function of a transmembrane protein, resulting in specific behavioral outcomes. In the Wernig lab, she aims to understand the molecular mechanisms by which neuronal identity is established and how its disruption leads to neurological diseases.

Yohei Shibuya
Postdoc Fellow
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I completed my PhD in Dr. TY Chang’s lab at Dartmouth College, where I studied cholesterol metabolism in health and disease. In the Wernig lab, my research focus is on studying neurological diseases in human neurons and other neural lineages. I am also interested in developing novel therapeutic approaches for treating incurable neurological disorders using reprogramming technology.

Yongjin Yoo
Postdoc Fellow
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Yongjin received his Ph.D. in functional genomics in 2018 from the Seoul National University, South Korea. For his Ph.D., he focused on genetic mutations of human neurological patients and its functional impacts. Yongjin joined the Wernig lab in October 2018. In the Wernig lab, he is interested in developing therapeutic methods for neurological patients and understanding disease mechanisms using human stem cells and neurons.


Wernig Lab Alumni

2020
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Angel Ayala
Master's Student
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Angel earned his B.S. in Biology at California State Polytechnic University, Pomona. As an undergraduate he studied the effects of nicotine on diabetic individuals. As a CIRM fellow at Stanford University, he is interested in using microglia cell replacement and stem cell technology as a potential therapeutic for neurological disorders. Unfortunately, COVID19 cut some of the last of his time he was planning to stay with us. We are proud of Angel that he got into the PhD program at UC Irvine where he moved during these challenging times of natural disasters of the year 2020. Good luck Angel!

Cheen Euong Ang
PhD student
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Cheen Euong Ang was a bioengineering PhD student in the Wernig lab. He spent his undergraduate career at McGill University, graduating with a B.Sc. in Chemistry with a focus in biological chemistry. Since coming to Stanford, Cheen Euong has been working on investigating the mechanisms of iN reprogramming and applying the iN platform in disease modeling and aging. Other than doing research in the lab, Cheen Euong has participated several scientific outreach programs such as the Stanford Biomedical Engineering Society undergraduate academic mentoring program and Stanford Institute of Medical Summer High School Student Research Program. Cheen moved on to do his postdoc in Xiaowei Zhuang at Harvard University in Cambridge, MA.

Christina Tan
Postdoc Fellow
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Graduating from UC Berkeley majoring in Biology with an honors in Neuroscience, and having worked as an MD at the Royal Melbourne Hospital, I have developed a particular interest in translational neuroscience. In the lab, I am investigating the efficacy of cell therapies for neurological disorders. I am currently working on microglia based therapies for major neurological diseases, including multiple sclerosis.

Daniel Haag
Postdoc Fellow
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I am a molecular biologist with a focus on neuro- and cancer biology. I am interested in using human iPSCs to develop new in vitro disease models, particularly for neuropsychiatric disorders and neurooncology. This led me to the Wernig lab where I started my postdoc to explore the advantages of direct neuronal reprogramming and the intricacies of step-wise differentiation of neural cell types. I am genetically engineering iPSC lines to generate complex genomic alterations and inducible mutations. Following differentiation into the corresponding disease-relevant tissue, I am puzzling together cellular phenotypes, transcriptional regulation, protein interactions, and epigenetic changes for a better understanding of the disease biology. In my spare time, I enjoy a new definition of chaos by my 2-year-old daughter.

Hiroko Nobuta
Postdoc Fellow
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Hiroko received Ph.D. from UCLA Neuroscience program in Jim Waschek's lab. She's currently a postdoc studying the disease mechanism of pediatric brain disorder Pelizaeus-Merzbacher Disorder, affecting oligodendrocyte development and myelination. She uses patient-derived iPS cells, gene targeting in iPS cells, and animal models.

Jackie Young
Administrative Associate
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I was an administrative associate for the Wernig Lab for a brief period in 2019.  I am a native San Franciscan and I love the bay area.  I received my undergrad from San Francisco State.  I am fluent inSpanish so if you ever need a Spanish lesson come by desk.  My husband and I have three beautiful childrenand during my time off I really enjoying spending time with my family.

Kevin Kumar
Resident fellow
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I grew up in Long Island, NY. I attended college at Cornell University majoring in Biological Sciences with a concentration in Neurobiology and Behavior. After graduation in 2009, I moved to Nashville, TN to join the Medical Scientist Training Program at Vanderbilt University where I earned a combined MD/PhD. In 2016, I started my residency in Neurosurgery at Stanford. In the Wernig lab, I am interested in developing microglia-based regenerative therapies for neurodevelopmental and neurodegenerative disorders.

Lingjun Meng
Postdoc Fellow
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I received my PhD from National Institute of Biological Sciences (NIBS) at Beijing, China. My PhD mentor is Dr. Xiaodong Wang, who is a chinese-born American biochemist best known for his work with cytochrome C on apoptosis. He is a member of United States National Academy of Sciences and Howard Hughes Medical Institute.

During my PhD stage, my major work is to try and find function of a protein named RIP3 in necrosis (other program cell death) pathway. I use human fetal neural stem cells to study mutation caused epigenetic rigidity in reprogramming process. A lot of patient diseases are caused by gene mutation, but we do not know which kind of cells and which site of mutate will cause disease. We try to work on neural stem cells to induce some point mutation to imitate brain cancer disease from reported mutation site in human patient. Then we will know which mutation site is the key and try to fix it by the biology method.

Minjeong Lee
Lab Admin
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Minjeong was the administrative associate for the Wernig Lab. We all loved her positive spirit that made our lab a happy place. We were fortunate to have her for a full year! During her time off, she loved hanging out with my family and trying out different recipes. She moved on to a full time position in business.

Moritz Mall
Postdoc Fellow
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Dr. Moritz Mall is a postdoctoral fellow in the lab. After studying biochemistry and molecular biology at the LMU in Munich and the ETH in Zurich he received his Ph.D. from the EMBL in Heidelberg for his mechanistic studies on mitotic cell division. Besides surfing Moritz’s passion is to understand the molecular mechanisms of cell fate determination during reprogramming, development and disease.

Nan Yang
Postdoc Fellow
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A striking feature of the mammalian nervous system is its enormous cellular diversity. The biological question that drives my research in long-term is to understand how the nervous system develops and achieves its extraordinary complexity. I would also like to leverage my expertise in lineage reprogramming, stem cell biology, and neurobiology to develop reprogramming-based human cell culture models and study the fundamental processes underlying the development and function of human nervous system under normal and pathological conditions. Outside the lab, I like spending my time cycling, rock climbing and hiking.

Qian Yi Lee
PhD Student
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I am interested in studying the mechanisms of direct lineage reprogramming of fibroblasts into neurons.

Ron Danziger
Postdoc Fellow
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I grew up in Australia where I completed an undergraduate degree in neuroscience and an MD at the University of Melbourne, Australia. I then completed my intern year at the Royal Melbourne Hospital.  I have a keen interest in stem cell therapeutics and their potential application in treating debilitating neurological conditions. My current research focus is on novel microglia based therapies that can potentially ameliorate disease progression in multiple sclerosis.

Samuele Marro
Basic Life Res Scientist
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With billions of neurons interconnected with many billions of synapses, our brain is the most complex object in the known universe. I like to think that I’m doing my part in understanding it. I use human neurons to study a synaptic protein called Neuroligin 4 that is not found in mice, therefore very complicated to study but at the same time extremely fascinating. When mutated Neuroligin 4 causes Autism and impairs the synaptic transmission of neurons. After leaving his prominent imprint on the lab he moved on to join the faculty at Mount Sanai School of Medicine in New York. Good luck Samuele, we will miss you!

Sarah Grieder
Research Assistant
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I am a Research Assistant in the Wernig Lab. My work mainly focuses on iPS-derived induced neurons to model human neuropsychiatric disorders. In my free time I love to read, sing and enjoy the California weather.

Soham Chanda
Postdoc Fellow
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Neuroligins are postsynaptic cell-adhesion molecules that play a major role in shaping synapse properties. My projects involve understanding the functional contributions of different Neuroligin isoforms, investigating the pathogenic mechanisms of autism-associated Neuroligin mutations, and applying this knowledge for neurological disease modeling in human neurons transdifferentiated from non-neuronal cells. My work combines fundamental biology with translational research using multidisciplinary approaches, e.g. cellular reprogramming, electrophysiology, imaging, gene-expression and biochemical analyses.

Virginia Trakul
Administrative Associate
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Virginia is a dentist that worked with underserved communities before taking time off to care for her family. She is happy to be the administrative associate for the Wernig lab. In her free time she enjoys reading, playing tennis, and spending time with her family. Unfortunately, due to COVID19 Virginia needed more time to care for her children and had to leave us. She was a delight to have around and we will dearly miss her!

Yingfei Liu
PhD Visiting Student
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Yingfei Liu is a Neurobiology PhD candidate from Xi`an Jiaotong University,China. She is studying here for two years as a Joint-Training Doctoral Program. Her previous research interest was the self-renewal and differentiation of the neural stem cells. Now She is studying the mechanisms of direct lineage reprogramming of fibroblasts into neurons. Yingfei was great to have in the lab. COVID19 also affected Yingfei's carreer. In the midst of great progress COVID19 precluded much of her continuing to work. She went back to China to arrange for her PhD defense and we are hoping to be able to continue to work with her in the future. Good luck Yingfei!

Wernig Lab Press

Wernig Lab Protocols & Recipes

Contact

We are always interested to hear from ambitious scientists and potential collaborators.

Marius Wernig
wernig@stanford.edu

Virginia Marie Trakul, Lab Admin
vtrakul@stanford.edu

Institute for Stem Cell Biology and Regenerative Medicine
Wernig Laboratory
265 Campus Drive G3141
Stanford, CA 94305
U.S.A.

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