Whitehead Institute for biomedical Research
The laboratory of Rudolf Jaenisch focuses on understanding epigenetics in normal development and in disease. Epigenetic regulation of gene expression is a key biological mechanism that affects how genetic information is converted into cellular phenotypes but does not alter the sequence of genes. His work has led to major advances in our understanding of embryonic stem cells and induced pluripotent stem cells (iPSCs) and their potential for disease modeling and therapy.
Background. Rudolf Jaenisch produced the first transgenic animals in the 1970. In the 80’s and 90’s his lab made many contributions to the understanding of cancer, neurological diseases and the role of DNA methylation in mammalian development using transgenic mice. The lab was one of three labs worldwide that reported in 2007 cells taken from mouse tails could be reprogrammed into iPSCs by over-expressing four master gene regulators. Later that year, the lab followed up by further manipulating iPSCs to treat sickle-cell anemia in mice, the first proof in principle of therapeutic use of such cells. In 2008, the lab reported that neurons derived from iPSCs successfully integrated into fetal mouse brains and reduced symptoms in a Parkinson’s disease rat model.
Disease Modeling. The Jaenisch lab focuses on understanding the genetic and epigenetic basis of familial and sporadic diseases. We combine patient-derived iPSCs with genome editing tools to develop sophisticated disease models and to devise therapeutic strategies. We study disorders such as Alzheimer’s and Parkinson’s disease, Rett Syndrome, Fragile X, cancer and Diabetes mellitus.
Epigenetics and Epigenome Editing. The lab is interested in various epigenetic mechanisms that control gene expression, including DNA methylation, histone acetylation, 3D chromatin interactions, and nuclear condensates. Recently, we have developed an integrating DNA methylation reporter and have investigated the effect of stochastic DNA methylation changes on enhancer function. Most recently, the lab has used CRISPR/Cas9 gene targeting to edit the epigenetic state of the mammalian genome. This is an exciting approach as it allows restoring normal expression of genes that have been epigenetically silenced without altering the DNA sequence. The lab has used epigenetic editing to correct the disease phenotype in neurons from patients with autism spectrum disorders such as Rett and Fragile X syndrome.
Coronavirus. Infection with SARS-CoV-2 may have very different consequences for the patient with some exhibiting no obvious disease and others suffering sever and highly variable symptoms. While infection of lung epithelial cells is thought to be responsible for severe illness it has become clear that also brain cells and other tissues are a serious target for the virus. The lab is using human stem cell technology to generate a broad range of cell types. The cells are exposed to virus infection as this will allow us to define the tropism of the virus and test for therapeutic interventions that would inhibit virus propagation in the key target cells.
Neural Crest Cells and Cancer. Neural crest cells (NCCs) arise at gastrulation and contribute to multiple cell types throughout the body. Dysfunction in neural crest lineages are responsible for many developmental disorders and cancers, including neuroblastoma and melanoma. To study the development of such diseases with human cells in vivo, we have generated human-mouse chimeras in which human stem cell derived NCCs are transplanted into gastrulating mouse embryos. The transplant functionally integrates into the mouse, resulting in chimeras with human cells occupying natural neural crest lineage niches. To date, our lab has modeled neuroblastoma with this platform by introducing cancer-inducing genetic modifications to the transplanted NCCs. Unlike conventional xenograft models, the neural crest chimera model uses an immune-competent host. The neural crest chimera model therefore uniquely permits the study of in vivo initiation and progression of human tumors within a fully functional immune system.
Founding Member, Whitehead Institute
Professor of Biology, MIT
Maisam (Maya) Mitalipova
Director Human Stem Cell Facility
Maya is originally from Almaty Kazakhstan. She obtained her PhD in Stem Cell Biology at Moscow Medical Genetics Institute, investigating human diseases using genetically engineered mouse embryonic stem cells (ESCs). During her postdoctoral training with Neal First at University of Wisconsin-Madison, Maya worked with bovine ESCs and by 1999, she had cloned two calves from fibroblasts by using nuclear transfer technology. From 2001-2003, Maya worked at BresaGen, Inc., where she studied Parkinson’s disease using ESCs. From 2003-2004, Maya was a Senior Research Scientist at University of Georgia-Athens working on genetic stability of human ESCs. In August 2005, Maya joined Whitehead Institute to open the first Human Stem Cell Laboratory at MIT. In close collaboration with the Jaenisch Lab, Maya has since then studied ESC biology and neurodegenerative diseases using human ESCs and iPSCs that she routinely and in large numbers generates for various labs. Besides her work at the Whitehead, for 11 years and until her passing away, Maya had been the sole caregiver for her mom who was diagnosed with Parkinson’s disease. She had learned Parkinson Disease from inside and out. Maya belongs to ancient Turkish ethnicity named Uyghurs, who are oppressed now in their homeland by Chinese government. Maya is an activist and spends her spare time to advocate for human rights of her people.
Styliani (Stella) Markoulaki
Stella completed her PhD at Tufts University School of Medicine working on mammalian egg activation. She joined the Whitehead Institute as a post-doctoral fellow, in Rudolf Jaenisch’s lab, in 2005, working in the fields of Somatic Cell Nuclear Transfer and in vitro Reprogramming untill 2009 when she transitioned into a Research Scientist position. In 2014, after taking a 1-year break to establish a new transgenic core facility at Switzerland’s ETH, she returned to the Whitehead. Her new position involved the establishment of WI’s Genetically Engineered Models Center (GEM; http://gem.wi.mit.edu), which she currently directs. Stella’s mission is to provide cutting edge methods to generate genetically edited mice for the Institute, as well as external biomedical institutes. In addition to many other research projects, Stella is currently collaborating with the Esvelt Lab at MIT to generate Lyme-resistant mice.
Administrative Lab Manager
Carrie joined the Jaenisch lab in 2009 as lab manager. Prior to that, Carrie conducted doctoral research in Bruce Baker’s lab studying the role of intersex in Drosophila sex determination and post-doctoral research in Jim Robert’s lab analyzing the regulation of p27Kip1 in mouse tumor models. She also worked as a lab manager in Richard Gardner’s lab, which studies ubiquitin-mediated regulation of nuclear protein quality control. As lab manager in the Jaenisch lab, Carrie collaborates with lab members to ensure the lab functions smoothly and helps facilitating research projects for post-docs and students. Carrie also oversees the mouse cell line and plasmid databases for the lab and contributes to research projects. For her dedication and help, Carrie has received the Whitehead Spirit Award and Appreciation Award.
Raaji has been working at the Whitehead Institute for over 24 years and joined the Jaenisch Lab 13 years ago. She keeps track of all the human cell lines the lab has generated over the years. As the lab’s safety representative, she ensures that the lab runs smoothly and is a safe place for everyone. Her contribution to several projects is overwhelming, as she had been working alongside many lab members over the years and is a go to person for everyone if one needs help with human pluripotent stem cell cultures. Raaji’s dedication and friendliness has won her numerous Whitehead Appreciation Awards. She is always happy to organize social events for the Lab and over the years, she and her family had been a great host for several Jaenisch Lab Parties.
Ruthie has been working with animals since 1978, when she joined the US Army, working in a research institute in Maryland specializing in infectious diseases, with animals such as monkeys, mice, guinea pigs and rabbits. Afterwards, she worked in a veterinary clinic with cats, dogs, and horses on Hawaii for three years. In 1985, the Jaenisch Lab was extremely lucky, when Ruthie started and excelled as the lab’s animal technician specializing in colony maintenance, tailing, dna extraction, hormone priming, setting up mice for timed pregnancy and pseudo pregnant females. Soon afterwards, she also joined Whitehead’s GEM Core Facility to create mouse models together with numerous laboratories that transformed the field. She won the Whitehead Spirit Award and several Whitehead Appreciation Awards and is the daily go-to person in the lab when mouse experiments need to be set up or don’t work. Ruthie is also famous for her generous and numerous gifts she gives to lab members and legendary parties at her home.
Dongdong is Jaenisch Lab’s histologist and has been with the lab for the past 16 years. During her time with Jaenisch Lab, Dongdong has been involved in multiple projects and publications, and performs critical lab tasks such as paraffin section, cryostat section, IHC, and cell culture. Dongdong is a dedicated member of Jaenisch Lab and has won the Whitehead Spirit Award and numerous Whitehead Appreciation Awards. Prior to joining Whitehead, she was a histologist at Boston Children’s Hospital and Massachusetts Institute of Technology.
I graduated from Boston University in 2008 with degree in Biomedical Engineering. I joined the Jaenisch lab as a full-time research technician in 2010. My responsibilities have evolved through the years as I have gained more experiences. I have rotated in helping different postdocs through their projects whenever more help is needed such as performing different molecular biology techniques and maintaining and differentiating cell cultures. I am now currently assisting postdoc Xin Tang with his project and also responsible for maintaining and differentiating neural progenitor cell lines which are used either in our lab or with collaborating labs.
Kristin graduated from Carleton College (Northfield, MN) in 2013 with a B.A. in Biology and then worked for 3 years as a post-baccalaureate researcher at the U.S. Food and Drug Administration. As a graduate student in the Jaenisch lab, she is developing a novel model of melanoma using human-mouse neural crest cell chimeras. Using this model, she hopes to find human-specific determinants of melanoma immune cell invasion and mechanisms of resistance to immunotherapy.
I graduated from EPHE in Paris with M.S. in system biology and completed my Ph.D at the University of Montreal under the supervision of Dr. Gilbert Bernier. Throughout my graduate studies, I specialized on the use of pluripotent stem cells to model diseases such as Familial Hypercholesterolemia, Alzheimer’s disease and age-related macular degeneration. My research in the Jaenisch Lab is focused on studying the impact of DNA methylation changes in Alzheimer’s disease brain on the initiation and progression of the disease. In addition, I use pluripotent stem cell technology to better understand how the number of CGG repeats in Fragile X-linked syndromes is affecting the transcription and further translation of FMR1.
Max completed a BSc and MSC in Molecular Life Sciences at Wageningen University in the Netherlands. Afterwards he pursued a PhD in the laboratory of Chad Cowan at the Harvard Stem Cell Institute, under the co-mentorship of Christine Mummery at Leiden University. His work there was focused on using human stem cells for disease modeling, by optimizing differentiation protocols and investigating mechanisms for cardiovascular and metabolic diseases. His present research in the Jaenisch lab is to study type 2 diabetes, by generating human metabolic tissues and tuning their insulin signaling response. He uses a range of techniques, including human stem cell differentiation, genome editing, molecular biology, biochemistry and -omics approaches to understand novel mechanisms of insulin resistance leading to diabetes.
I am a cellular and molecular biologist with an emphasis on human genetics, gene regulation, and the genetic basis of human disease. I received my Ph.D. in Cellular and Molecular Biology from the University of Pennsylvania, where I studied the role of TMEM106B in conferring genetic risk for many neurodegenerative conditions. My current research goals are to 1) develop more physiologically-relevant hiPSC-derived neuronal and glial cell models for studying neurodegenerative disease, 2) better understand the mechanisms underlying common genetic risk factors for Alzheimer's and Parkinson's disease, and 3) investigate the role of liquid-liquid phase separation in the pathogenesis of Alzheimer's and Parkinson's disease.
I am a biomedical engineer in the labs of Rudolf Jaenisch (MIT and the Whitehead Institute) and David Mooney (Harvard and the Wyss Institute), and I am focused on developing disease models and regenerative medicine therapeutic strategies for inflammatory diseases. My current work aims to understand the role of the adaptive immune system in regulating the function of metabolic tissues and then engineer immunomodulatory strategies to recruit and activate regulatory immune cells in in vivo adipose tissue.
Marine Krzisch completed her PhD in neurosciences in the University of Lausanne in 2014. During her PhD, she was studying the effect of synaptic activity on adult-born neuron integration into the circuitry of the mouse hippocampus at University of Lausanne, in Switzerland. She is now interested in generating better in vivo models for neurological diseases by transplanting neural cells differentiated from patient-derived iPSC into the mouse brain.
I completed my Ph.D. at the University of Toronto in the laboratory of Laurence Pelletier, working on dissecting molecular mechanisms of centrosome biogenesis and its link to human diseases such as cancer and microcephaly. As a Canadian Institutes of Health Research (CIHR) postdoctoral fellow in the Jaenisch lab, I aim to use human stem cell-based systems to investigate the molecular pathogenesis of neurodegenerative diseases with a primary focus on Rett syndrome. Along with my background in advanced imaging technologies, I will integrate novel biophysical concepts and cutting-edge technology for genetic and epigenetic analyses to characterize the role of phase separation in transcriptional regulation and to determine how abnormities in this process lead to brain disease progression. A long-term goal of my research is to investigate whether small molecules can be identified that correct pathological phase separation. Thus, it may be possible to develop a novel therapeutic treatment for human brain disorders.
My research focuses on signaling pathways and epigenetic mechanisms regulating stem cells differentiation and maturation into functional endodermal cell types such as hepatocytes and endocrine pancreatic cell types. Organoid culture, transcriptional and epigenetic profiling, chemical screens, and functional characterization (in vitro and in humanized mice) are commonly utilized approaches to gain a systematic understanding of concerned cell types. The knowledge gained are used to recapitulate both normal developmental processes and disease pathology to provide insights to regenerative medicine and chronic diseases (liver diseases and diabetes) that are otherwise difficult to study. Before joining the Jaenisch lab, I worked on cell adhesion mechanisms underlying gastrulation and colorectal cancer.
I completed my graduate studies at the Medical College of Wisconsin (Go Packers!). My research focused on how enteroviruses interact with the host cell’s autophagic pathway. As a postdoc in the Jaenisch lab I am trying to understand how neurotropic viruses access the brain and how the immune cells of the brain respond to infection once it is there. To address the first question we use human stem cells to produce the cells that comprise the blood brain barrier. To address my second question we have generated cerebral organoids and microglia (which are the primary immune cells of the brain) from human stem cells and use this as a model system to study infection of the central nervous system. In response to the COVID-19 pandemic I shifted my research from modeling neurotropic viruses in the brain to examining the tropism and transcriptional response to Sars-CoV-2 using stem cell derived lung, brain, liver, and endothelial cells.
Jian is a Helen Hay Whitney Fellow, NIH K99/R00 Pathway to Independence Awardee working at the intersection of computational biology and stem cell biology at Dr. Eric Lander’s lab at the Broad Institute of MIT and Harvard and Dr. Rudolf Jaenisch’s lab at the Whitehead Institute for Biomedical Research at MIT. Jian’s research interests center around methods of single-cell genomics and mechanisms of cellular programming, reprogramming, and maternal-fetal tolerance. Jian completed his Ph.D. training with immunologist and stem cell biologist Dr. Hongkui Deng and was the valedictorian at Peking University.
I received systematic engineering training at the Huazhong University of Science and Technology and Yale University. During my doctoral training in the laboratory of Gong Chen at Pennsylvania State University, I studied genetic and environmental factors regulating synaptic signal transmission, and discovered that the neuronal gene KCC2 plays a major role in the functional deficits observed in Rett syndrome, a severe neurodevelopmental disorder. In the Jaenisch Lab, I combined CRISPR gene editing and human stem cell technologies to develop a drug-screening platform and identified novel compounds that modulate the expression level of the KCC2 gene. Currently, I am elucidating the molecular pathways underlying KCC2 gene regulation. Moreover, I leverage the gene-specific drug discovery strategy I pioneered to investigate a number of neurodevelopmental disorder risk genes. The long-term goal of my research program is to develop therapeutics that enable rigorous testing of the hypothesis that neurological disorders are reversible even after disease onset. I am also a proud recipient of the Bridge to Independence career transition grant from the SFARI.
I completed my Biology degree with a concentration in Developmental Biology and Genetics at The Pennsylvania State University before undertaking my PhD in Neuroscience in the laboratory of Arin Bhattacharjee at the State University of New York at Buffalo. My work there was focused on the role of large-conductance potassium channels in peripheral pain, including inflammatory and neuropathic pain. My present research focuses on understanding molecular changes in neurodevelopmental disorders, including Autism Spectrum Disorder.
I graduated from Heidelberg University School of Medicine, Germany. My research focused on spontaneous electrical activities in microglia using the patch clamp technique. In the Jaenisch lab, I am developing new tools to study microglia phagocytosis in the healthy brain and in the context of Alzheimer’s Disease. Towards this goal, I am combining stem cell technologies, including human brain organoids, genome engineering, biochemistry and LCMS based proteomics. It is hoped that these insights will further illuminate the role of microglial phagocytosis in health and disease and its contribution to AD pathogenesis and progression.
I obtained my PhD from University of Illinois at Urbana-Champaign, advised by Dr. Andrew Belmont. My PhD research focused on genomic and cytological dissection of nuclear compartmentalization. We developed TSA-Seq and TSA-Seq 2.0 for genome-wide mapping of chromosomal distances relative to defined nuclear compartments/bodies, such as nuclear speckles and nuclear lamina. My work revealed new principles of 3D genome organization and their effects on gene expression regulation. In the Jaenisch lab, I am interested in studying epigenetics and nuclear organization in the nervous system and how their misregulation leads to diseases. Using stem cell technologies, mouse models, genome editing, biochemistry and sequencing, I hope to further understand the regulation and roles of key genes/proteins involved in neurological disorders such as the Rett syndrome, presumably paving the road to cure.
Visiting Scholars and Students
Li Y, Wang H, Muffat J, et al. Global transcriptional and translational repression in human-embryonic-stem-cell-derived Rett syndrome neurons. Cell Stem Cell. 2013;13(4):446‐458. doi:10.1016/j.stem.2013.09.001
Ma, H., Wert, K.J., Shvartsman, D., Melton, D.A., and Jaenisch, R. (2018). Establishment of human pluripotent stem cell-derived pancreatic beta-like cells in the mouse pancreas. Proc Natl Acad Sci U S A 115, 3924-3929.
Tang X, Drotar J, Li K, et al. Pharmacological enhancement of KCC2 gene expression exerts therapeutic effects on human Rett syndrome neurons and Mecp2 mutant mice. Sci Transl Med. 2019;11(503):eaau0164. doi:10.1126/scitranslmed.aau0164
Svoboda DS, Barrasa MI, Shu J, et al. Human iPSC-derived microglia assume a primary microglia-like state after transplantation into the neonatal mouse brain. Proc Natl Acad Sci U S A. 2019;116(50):25293‐25303. doi:10.1073/pnas.1913541116
Epigenetics and Epigenome Editing
Creyghton MP, Cheng AW, Welstead GG, et al. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci U S A. 2010;107(50):21931‐21936. doi:10.1073/pnas.1016071107
Liu, X.S., Wu, H., Krzisch, M., Wu, X., Graef, J., Muffat, J., Hnisz, D., Li, C.H., Yuan, B., Xu, C., et al. (2018). Rescue of Fragile X Syndrome Neurons by DNA Methylation Editing of the FMR1 Gene. Cell 172, 979-992 e976.
Song Y, van den Berg PR, Markoulaki S, et al. Dynamic Enhancer DNA Methylation as Basis for Transcriptional and Cellular Heterogeneity of ESCs. Mol Cell. 2019;75(5):905‐920.e6. doi:10.1016/j.molcel.2019.06.045
Neural Crest Cells and Cancer
Cohen MA, Wert KJ, Goldmann J, et al. Human neural crest cells contribute to coat pigmentation in interspecies chimeras after in utero injection into mouse embryos. Proc Natl Acad Sci U S A. 2016;113(6):1570‐1575. doi:10.1073/pnas.1525518113
Cohen, M.A., Zhang, S., Sengupta, S., Ma, H., Bell, G.W., Horton, B., Sharma, B., George, R.E., Spranger, S., and Jaenisch, R. (2020). Formation of Human Neuroblastoma in Mouse-Human Neural Crest Chimeras. Cell Stem Cell 26, 579-592 e576.