The discovery of the CRISPR/Cas9 system has led to a revolution in genome editing technology. The ease of gene targeting and manipulation with this approach and its derivatives have unlocked a plethora of previously unimaginable experimental areas within all disciplines of biomedical research. In this webinar, we will hear from experts in the field about the most cutting-edge applications of CRISPR/Cas9 targeting in the study of normal and malignant hematopoiesis, and how these approaches might one day benefit a wide range of patients with blood disorders.
Chad Cowan received his BA and BS, with honors, from Kansas University in 1995 and 1996. He received his PhD, from the University of Texas Southwestern at Dallas. He subsequently completed a postdoctoral fellowship with Professor Douglas Melton at Harvard University.
Our research is focused on understanding the molecular underpinnings of metabolic diseases such as type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD). Metabolic diseases such as T2DM and CAD are responsible for an increasingly large burden of morbidity and mortality worldwide, afflicting hundreds of millions of people. The development of new and effective treatments for these diseases requires the identification and validation in humans of novel disease mechanisms. Recent advances in human genetics have begun to explicate the heritable susceptibility to metabolic diseases; to date, genome-wide association studies in humans have identified more than 30 chromosomal loci strongly linked to T2DM, 95 loci to blood lipid levels, and 25 loci to CAD. Next-generation sequencing studies targeting the “exome” and attempting to directly identify causal genes are underway. We seek to convert novel genetic findings into the knowledge needed to develop therapies for patients. Our approach to linking human genotypes to human phenotypes has three key steps. The first is to perform human genome editing to introduce disease-associated gene mutations and DNA variants into human pluripotent stem cells (hPSCs). The second is to differentiate and engineer hPSCs into tissue types relevant to disease in order to develop ex vivo models of disease. The third is to perform functional assays in the genetically modified (and control) differentiated tissues to obtain pathophysiological insights. Once we have identified disease relevant phenotypes we plan to use our human cell-based models of disease to perform genetic and drugs screens to develop novel therapeutics.
Dr. Ebert is an Assistant Professor of Medicine at Harvard Medical School. He received a bachelor's degree from Williams College, a doctorate from Oxford University on a Rhodes Scholarship, and an MD from Harvard Medical School. He completed a residency in Internal Medicine at Massachusetts General Hospital and a fellowship in Hematology/Oncology at the Dana-Farber Cancer Institute before pursuing postdoctoral research at the Broad Institute.
We study the biology and treatment of cancer using hematopoiesis as a model system. The laboratory employs a range of genomic technologies as well as classical cellular and molecular biology approaches to investigate the biology of specific human diseases, particularly hematopoietic malignancies and disorders of red blood cell production. A major focus of the laboratory is the myelodsyplastic syndrome (MDS), a pre-malignant disorder of hematopoietic stem cells that progresses to acute leukemia. In recent work, we identified a gene that plays a central role in the pathophysiology of the 5q- syndrome, a subtype of MDS. Our findings revealed a molecular link between the 5q- syndrome and congenital bone marrow failure syndromes such as Diamond Blackfan Anemia. We are also actively involved in the identification and development of small molecules that could be useful for the treatment of cancer and hematologic disorders. We are studying compounds that induce fetal hemoglobin and could be useful for the sickle cell anemia. In addition, we are working on the identification and characterization of compounds that alter hematopoietic differentiation that could be useful for the treatment of cancer and non-malignant hematopoietic disorders.
Moderated by: Eirini Papapetrou, Icahn School of Medicine at Mount Sinai
Chromosomal deletions associated with human disease are common in normal and cancer genomes and may constitute an important component of the “missing heritability” of complex diseases and the “dark matter” of cancer genetics. Unlike translocations or point mutations, chromosomal deletions are difficult to study because physical mapping in primary patient material is limited by the rarity of informative cases and incomplete conservation of synteny complicates their modeling in mice.
We developed an approach to model disease-related chromosomal deletions in human iPSCs. By using modified Cre-loxP and CRISPR/Cas9 technologies we can engineer hemizygous deletions of specific chromosomal fragments. These allow us to functionally map disease phenotypes and identify candidate disease genes through phenotype-rescue screens.