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.