About

Rudolf Jaenisch is a Professor of Biology at MIT, a Core Member of the Whitehead Institute, and a Member of the Institute of Medicine. His research focuses on understanding the epigenetic regulation of gene expression in mammalian development and disease. He uses pluripotent cells, including embryonic stem (ES) and induced pluripotent stem (iPS) cells, to study the genetic and epigenetic basis of human diseases such as Parkinson’s, Alzheimer’s, autism, and cancer. His work emphasizes the importance of embryonic stem cells, which have the potential to generate any cell type in the body, for regenerative medicine. He studies how somatic cells reprogram to an embryonic pluripotent state and uses patient-specific pluripotent cells to investigate complex human diseases. Rudolf Jaenisch has made significant contributions to the field of biomedical research, earning numerous awards including the Franklin Institute Benjamin Franklin Medal, the Otto Warburg Medal from the German Society for Biochemistry and Molecular Biology, and the National Medal of Science from the NSF.

Research topics

• Biology
• Genetics
• Cell biology
• Computational biology
• Immunology
• Virology
• Cancer research
• Internal medicine

Selected publications

• Heritable immunization of mice against Lyme disease enables ecological disease prevention

  Nature Communications · 2026-04-28

  articleOpen access

  Heritable immunization is a promising approach to controlling infectious diseases by embedding immunity directly into the genomes of wild species that spread human pathogens. Here, we report the genetic engineering of Mus musculus to genomically encode a single-chain antibody against Borrelia burgdorferi, the causative agent of Lyme disease. After optimization of the antibody format, engineered mice stably produce a LA-2 scFv-albumin fusion protein targeting the Borrelia outer surface protein A (OspA) across multiple generations, demonstrating robust heritability and stability of gene expression. Following sequential challenges with infected and uninfected ticks, heterozygous mice exhibit strong resistance to infection, effectively interrupting the Borrelia burgdorferi disease transmission cycle. Having recently established protocols to genetically engineer the white-footed mouse Peromyscus leucopus, a key reservoir of Lyme disease, these findings demonstrate the feasibility of heritable immunization as a potential strategy for mitigating Lyme disease transmission in the environment. Engineered reservoir immunity may offer a promising approach to controlling vector-borne and zoonotic disease.

  PublisherOA PDFDOI

• A human blood-brain barrier model reveals pericytes as critical regulators of viral neuroinvasion

  iScience · 2025-12-13 · 1 citations

  articleOpen accessSenior author

  cellular interactions at the BBB. We used this model to evaluate the pathological consequences of BBB exposure to highly neuroinvasive flaviviruses. Our results identify a previously undescribed role for NCC-PCs in maintaining BMEC barrier integrity during infection and reducing the spread of viral infection to the CNS.

  PublisherDOI

• Oxidative Stress and Interferon Signaling Drive Differential Pathogenesis of Ancestral and Contemporary Zika Viruses in Human Cerebral Organoids

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-12 · 2 citations

  preprintOpen access

  Neurotropic Zika viruses (ZIKV) cause serious human disease with pandemic potential. Pathogenesis severities resulting from Asian/American versus African ZIKV lineage infections range from mild to severe, respectively; however, mechanisms underlying differential ZIKV pathogenesis remain unclear, as do effective therapeutic strategies. The limitations of mechanistic understanding are due in part to the challenges of comparing data generated in disparate experimental models, as well as approaches that did not test both ancestral and contemporary ZIKV infections. The goal of this work was to define differential pathogenesis mechanisms among ancestral and contemporary ZIKVs by direct infection comparisons using a relevant human stem cell-derived cerebral organoid experimental model. While Asian/American ZIKV lineage infections enhanced antiviral and interferon gene expression responses that correlated with viral RNA clearance from organoid ventricles, ancestral African lineage ZIKV infections enhanced apoptotic and stress response signaling that correlated with diminished STAT2 signaling protein levels, ongoing ZIKV replication, and production of damaging reactive oxygen species (ROS). We discovered that, surprisingly, severe ancestral Zika virus pathogenesis was dramatically reduced by Trolox, a hydroxyl radical scavenger antioxidant, thereby confirming ROS imbalance as a major pathogenesis driver. These results demonstrate that ZIKV lineage infections and pathogenesis are differentiated by their signaling responses and suggest that preventing or controlling hydroxyl radical imbalance may offer therapeutic benefits to address microcephaly and Congenital Zika Virus Syndrome. One Sentence Summary: Differential signal transduction responses to lineage-specific Zika virus infections cause reduction-oxidation imbalance-mediated pathogenesis that is blocked by Trolox, an antioxidant.

  PublisherOA PDFDOI

• Rapid iPSC inclusionopathy models shed light on formation, consequence, and molecular subtype of α-synuclein inclusions

  Neuron · 2025-02-01

  erratumOpen access

  Publisher of over 50 scientific journals across the life, physical, earth, and health sciences, both independently and in partnership with scientific societies including Cell, Neuron, Immunity, Current Biology, AJHG, and the Trends Journals.

  PublisherDOI

• Rett Syndrome: Thinking Beyond Brain Borders

  Advances in experimental medicine and biology · 2025-01-01 · 3 citations

  reviewSenior author
  PublisherDOI

• Author response for "Human iPSC-derived microglia integrate into cerebral organoids and assume an in vivo-like phenotype"

  2025-08-25

  peer-reviewSenior author
  PublisherDOI

• Functional genomic dissection of MS risk loci reveals convergence of cis and trans gene regulatory mechanisms in microglia

  medRxiv · 2025-06-20

  preprintOpen access

  Summary Neurological diseases (NDs) are a major source of unmet medical need, and translational insights have been hampered by complex underlying pathophysiologies and limitations of experimental models. Noncoding single nucleotide polymorphisms (SNPs) at hundreds of loci have been linked to ND risk by genome-wide association studies (GWAS), but the causal genes and pathways are largely unknown. Despite the multicellular pathology of complex traits like multiple sclerosis (MS), functional studies that aim to characterize the molecular impact of disease-associated SNPs often investigate all SNPs linked to disease in the same cellular context. Here, we combine a computational approach to predict the pathogenic cell type of individual risk loci with functional CRISPR perturbation studies in iPSC-derived microglia cells (iMGLs). ND SNP enrichment in cell type-specific enhancers is similar between primary and iPSC-derived cells, and mechanistically supported by shared enhancer-promoter interactions. We apply a novel Perturb-seq platform to interrogate MS risk SNPs in iMGL, identifying likely cis -acting causal risk genes at 5 of 9 loci, as well as downstream differentially expressed genes (DEGs). Despite being found in trans to MS risk SNPs, downstream DEGs are substantially enriched for MS heritability. Downstream DEGs from all 5 target genes show significant overlap, converging on genes related to cytokinesis, phagocytosis, and mitochondrial metabolism. We then compared downstream DEGs to gene expression patterns observed in MS patient tissue studies and observed marked similarities, demonstrating that genes dysregulated as the result of GWAS loci perturbation mirrored effects observed in microglia found in MS patient lesions. Collectively, these results demonstrate that cell type aware functional studies can be used to translate ND SNP associations into mechanistic insights and reveal novel convergent biological mechanisms underlying complex traits.

  PublisherOA PDFDOI

• Human iPSC‐Derived Microglia Integrate Into Cerebral Organoids and Assume an In Vivo‐Like Phenotype

  European Journal of Neuroscience · 2025-11-01 · 4 citations

  articleOpen accessSenior authorCorresponding

  Microglia, the brain-resident macrophages, are critically involved in numerous physiological and pathological brain processes, including neoplasms, epilepsy, and neurodegeneration. However, investigating microglial function is notoriously difficult because they are extremely sensitive to changes in their environment and drastically alter their transcriptional state and morphology once they are isolated from the brain and cultured in vitro. In vivo experiments in mice are likewise limited because of vast differences between mouse and human microglia, particularly regarding the expression of disease-associated genes. To overcome this issue, we developed a highly controlled in vitro cerebral organoid platform where human microglia adopt an in vivo-like phenotype. This approach allows long-term studies and high-throughput analysis of in vivo-like human microglia suitable for disease modeling and drug testing.

  PublisherOA PDFDOI

• Exploring the complexity of MECP2 function in Rett syndrome

  Nature reviews. Neuroscience · 2025-05-13 · 16 citations

  reviewSenior author
  PublisherDOI

• A novel human blood-brain barrier model reveals pericytes as critical regulators of viral neuroinvasion

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-03

  preprintOpen accessSenior authorCorresponding

  Abstract The blood-brain barrier (BBB) plays a vital role in regulating the passage of biomolecules between the bloodstream and the central nervous system (CNS) while also protecting the CNS from pathogens. Pericytes reside at the interface between the endothelial cells that form the vessel walls and the brain parenchyma. These cells are critical for maintaining BBB integrity and play key roles in regulating vessel permeability, blood flow, and immune cell migration. In this study, we developed a novel serum-free protocol to generate neural crest cell-derived pericytes (NCC-PCs) from human pluripotent stem cells (hPSCs). These NCC-PCs enhance BMEC barrier function and can be co-cultured with hPSC-derived brain microvascular endothelial cells (BMECs) in a contact co-culture BBB model that recapitulates the in vivo cellular interactions at the BBB. We used this model to evaluate the pathological consequences of BBB cell infection by highly neuroinvasive flaviviruses. Our results identify a previously undescribed role for NCC-PCs in maintaining BMEC barrier integrity during infection and reducing the spread of viral infection to the CNS.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R37HD045022

  NIH · $7.5M · 2018

• NIH Grant R01NS08853801

  NIH · $1.0M · 2019

• NIH Grant R01NS088538

  NIH · $5.0M · 2020

• NIH Grant R01CA087869

  NIH · $8.2M · 2011

• Transcriptional condensates, epigenetic editing and Rett Syndrome

  NIH · $7.4M · 2014–2025

Frequent coauthors

• Konrad Hochedlinger

  Harvard Stem Cell Institute

  163 shared

• Kevin Eggan

  Broad Institute

  130 shared

• Richard A. Young

  113 shared

• Arlene H. Sharpe

  Massachusetts General Hospital

  92 shared

• Albert W. Cheng

  Arizona State University

  92 shared

• Caroline Beard

  Whitehead Institute for Biomedical Research

  88 shared

• Laurie Jackson‐Grusby

  Harvard Stem Cell Institute

  85 shared

• Styliani Markoulaki

  Northwestern University

  80 shared

Labs

• Rudolf Jaenisch LabPI

Education

• M.D., Medicine

  University of Munich

  1967

Awards & honors

• Otto Warburg Medal, 2014
• Medicine Medal, New York Academy, 2013
• Benjamin Franklin Medal, Franklin Institute, 2013
• National Medal of Science, 2011
• National Medal of Science, 2010