Hematopoietic Stem Cells and Immunology
Janis Abkowitz (Medicine/Hematology)
Dr. Abkowitz studies the in vivo behavior of hematopoietic stem cells (HSC) in transplantation models and in parabiotic mice. She has shown that the divergent patterns of clonal contribution in individual animals following limiting dilution transplantation can be explained by the stochastic differentiation of HSC and has investigated the mechanism by which neoplastic HSC dominate in the myeloproliferative disorders. She also studies the pathogenesis and therapy of erythroid marrow failure and the role of heme export in this process.
Chris T. Amemiya, PhD (Benaroya Research Institute)
In my research lab we are interested in the origins of novelty and innovation in vertebrates, with special emphasis on the adaptive immune system and vertebrate bauplan. We use whatever tools are necessary to address fundamental biological questions, particularly large-insert cloning, comparative genomics, computational biology and developmental biology. Although our research is fundamental in scope, we are always looking for ways in which our findings may be relevant and applicable to biomedical research. Our most recent work focuses on stem cell biology in a nonmammalian vertebrate model system, the sea lamprey. We have discovered that the sea lamprey jettisons roughly 20% of its genome during embryonic development, the deleted DNA encompassing both noncoding as well as coding sequences. This rampant loss of chromatin in all resultant somatic lineages raises several questions with respect to mechanism of loss and, more importantly, to the partitioning of gene functions in germline and somatic lineages and the maintenance of genetic totipotency. This work is interrelated with our research on a rearranging gene system that is involved in adaptive immune recognition in lampreys but also requisite for building the early embryo. We are interested in understanding the role of global genome dynamism described above in the evolution and development of this rearranging gene system.
Pamela S. Becker, MD, PhD (Medicine/Hematology)
Hematopoietic stem cell transplant
C. Anthony Blau, MD (Co-director, ISCRM; Medicine/Hematology)
This lab works on developing small molecule control mechanisms to regulate the number of cells in a patient after transplant, thereby increasing or decreasing cell number based on clinical end points.
Laura Crisa, MD, PhD (Metabolism, Endocrinology and Nutrition)
Our research focuses on characterizing immune cells and vascular cell components that favor pancreatic tissue engraftment at transplantation sites. Specifically, we are interested in identifying survival, proliferative and or maturation signals that vascular cells and leukocytes may deliver to pancreatic islet cells or their progenitors. Knowledge gained from this research may help to define the best possible transplant microenvironment supporting engraftment of islet tissue and possibly unveil novel cellular signals that can influence the maturational program of pancreatic islet progenitors. This line of studies has a direct impact on islet cell replacement strategies as treatment for patients with Type 1 diabetes.
Mary L. (Nora) Disis, MD (Medicine/Oncology)
Our group is developing a vaccine targeting proteins upregulated in cancer stem cells with the aim of eradicating these cells in early tumors.
Sergei Doulatov, PhD (Medicine/Hematology)
Think about the last time you heard someone searching for a compatible bone marrow donor. Hematopoietic stem cells (HSCs) are rare cells that can fully reconstitute the blood system after bone marrow transplantation. The donor has to immune-matched and it is unlikely that two unrelated individuals will be matched. Is there an alternative way to create these valuable blood cells? In 2006, a group of Japanese scientists found a way to create pluripotent stem cells by "reprogramming" any cell in the body. These are called induced pluripotent stem cells (iPSCs) and they can give rise to any tissue in the body. Our lab is working to generate immune-matched blood cells from pluripotent stem cells.
Just as iPSCs from healthy individuals can be used to create healthy matched blood cells, iPSCs from patients with blood disorders make diseased blood cells. We can collect bone marrow cells from patients, but there are often too few of these cells to help us understand what goes wrong in these diseases. We are using iPSCs from patients with blood disorders to uncover causes of these diseases and to discover candidate therapeutics using high-throughput drug screens. This allows us to screen thousands of chemical compounds at a time to find ones that can rescue the cellular defect. Our previous work has identified a small molecule therapeutic for Diamond Blackfan anemia - a rare inherited bone marrow disorder. This molecule turns on a cellular pathway called autophagy. It is a damage control pathway that allows cells to recycle damaged components. We would like to understand the role that this pathway plays in normal blood and in diseases, such as anemias.
Zhijun Duan, PhD (Medicine/Hematology)
The focus of our research is on understanding the mechanisms underlying development and tumorigenesis through deciphering the structure-function relationship of mammalian genomes. We have developed a series of high throughput methods for mapping three-dimensional (3D) genome architecture globally or locally. Recently, in collaboration with the investigators in the University of Washington Center for Nuclear Organization and Function (UW-CNOF), we developed a single-cell Hi-C method for characterize the 3D genome architecture in thousands of single cells in a massively parallel fashion. We have used these tools to dissect the dynamics of 3D genome organization in the context of a variety of biological systems. One of our current focuses is to characterize the nuclear morphology-associated 3D genome rearrangement and epigenetic programming during blood cell maturation and the pathogenesis of hematologic disorders.
Andrew G. Farr (Biological Structure & Immunology)
Thymic epithelial differentiation. The focus of this laboratory is to understand the developmental program of thymic epithelial cells. This knowledge is critical for developing strategies to enhance the recovery of thymic epithelium from the conditioning strategies employed in bone marrow transplantation, for the reversal of age-related senescence of thymic function, and to understand how the thymus contributes to the establishment and maintenance of self-tolerance. Approaches include the identification of thymic epithelial populations with regenerative capacity in vitro or in vivo and the use of modified embryonic stem cells as candidate thymic epithelial progenitor cells. Information gained from murine studies will be translated to the human.
Cecilia Giachelli (Bioengineering)
My lab is interested in applying stem cell and regenerative medicine strategies to the areas of ectopic calcification, tissue engineering, biomaterials development and biocompatibility.
Marshall Horwitz, MD, PhD (Pathology)
The Horwitz laboratory has a longstanding interest in genes and mechanisms leading to hematological malignancy. More recently, the lab has focused attention on using somatic mutations to infer cell lineage in order to better understand how stem cells contribute to development, tissue regeneration, and cancer.
Siobán Keel, MD (Medicine/Hematology)
The Keel Laboratory aims to understand normal and abnormal red blood cell development, with a focus on determining why red blood cell maturation fails in mice lacking FLVCR, and determining the role of the sodium-phosphate import protein, PiT-1, in hematopoiesis.
Hans-Peter Kiem (Fred Hutch)
The main focus of our lab is to study stem cell biology and stem cell gene transfer with the goal of developing novel stem cell based treatment strategies for patients with genetic, infectious and malignant diseases. Most of our work has been with hematopoietic stem cells (HSCs) although more recently we have also initiated studies using embryonic stem (ES) cells. Our lab has focused on studying HSC biology and gene transfer in large animal models.
The following are some of the projects in the lab: 1) HSC characterization in large animal models, 2) development of improved vector systems and transduction methods for HSC gene transfer, 3) analysis of integration site patterns of different retroviruses, 4) analysis of the clonal composition of hematopoiesis after transplantation of gene-modified HSCs, 5) studies of drug resistance gene therapy approaches in large animal models, 6) development of anti-HIV gene therapy strategies in the nonhuman primate SHIV model, 7) development of efficient HSC expansion strategies, 8) gene targeting and correction in HSCs, 9) ES cell studies and reprogramming in the nonhuman primate model.
We have now also 2 clinical gene therapy studies funded by the NIH. One study aims at introducing the MGMTP140K resistance gene into autologous CD34+ in patients with glioblastoma to make the hematopoietic system resistant to the myelosuppressive effects of BCNU and temozolomide chemotherapy, thus hopefully allowing the safe administration of more intensive chemotherapy and improved survival. The other clinical study aims at correcting the genetic defect in patients with Fanconi anemia.
Hao Yuan Kueh, PhD (Bioengineering)
Our lab studies how immune cells make fate decisions, both as they develop from stem and progenitor cells, and as they respond to antigens. We combine live cell imaging, mathematical modeling, as well as modern genetic, biochemical, and high throughput approaches to dissect the molecular circuitry underlying fate control at the single cell level. Our work will lay foundations for engineering immune cells to treat cancer and other life-threatening diseases.
André Lieber, MD, PhD (Medical Genetics, Pathology)
The main objective of research in Dr. Lieber's laboratory is to develop new approaches for cancer therapy.
Ray Monnat, PhD (Pathology, Genome Sciences)
Our research focuses on human RecQ helicase deficiency syndromes such as Werner syndrome; high resolution analyses of DNA replication dynamics; and the engineering of homing endonucleases for targeted gene modification or repair in human and other animal cells.
Thalia Papayannopoulou, PhD (Medicine/Hematology)
Dr. Thalia Papayannopoulou's research program aims to understand the mechanisms whereby hematopoietic stem cells home to bone marrow following transplantation, and how they traffic between the marrow and the blood stream under normal and perturbed hematopoiesis. A particular focus is on the characterization of the hematopoietic stem cell niche. In addition, Papayannopoulou lab studies erythroid cell development during the embryonic, fetal and adult stages of development.
Robert Richard (Medicine/Hematology)
My research involves the development of virus vectors that 1) block HIV replication and 2) correct disorders of red blood cells. In addition, methods to improve engraftment of genetically modified cells are being tested. Following pre-clinical testing, my group intends to test foamy virus vectors that express anti-HIV proteins in patients with HIV-associated lymphoma.
David Russell (Medicine/Hematology)
David Russell’s laboratory is studying the genetic manipulation of stem cells. In particular, viral vectors are used to both introduce genes and modify cellular genes in several types of stem cells. This includes research on genetic diseases such as brittle bone disease and acquired diseases such as AIDS that can in principle be treated with genetically modified “adult” stem cells. A major area of investigation is the genetic engineering of human embryonic stem cells. Over the last decade, Dr. Russell’s laboratory has developed a novel method for specifically changing chromosomal genes in human stem cells that is far more efficient than any other existing technique. Research is under way with human embryonic stem cells in order to make them suitable for clinical use. A major focus is to overcome the immunological barriers that prevent cultured stem cell lines from being used in transplantation. Dr. Russell is using this novel “gene targeting” approach to engineer the genes that determine whether a cell will be rejected after transplantation, in order to create patient-specific stem cells from existing stem cell lines. These cells will be matched to patients, just as bone marrow cells are matched prior to bone marrow transplantation. This strategy will overcome the need for “therapeutic cloning” in order to generate patient-specific stem cells, which is a highly controversial and extremely complex technique requiring the cloning of human embryos. Each cell line generated by Dr. Russell’s approach will be compatible with a significant percentage of the population, allowing it to be used in multiple patients to treat any disease where embryonic stem cells are being evaluated. This would overcome one of the most significant barriers to the therapeutic use of stem cell lines, and move this technology into clinical trials.
April Stempien-Otero, MD (Medicine/Cardiology)
We are interested in the role of bone marrow derived cells in cardiac repair and regeneration. Our specific research lies in how bone marrow derived cells direct the accumulation of excess collagen (fibrosis) in the heart and how that process can be reversed to allow optimal endogenous or exogenous cardiac regeneration. Using a human model we are testing the hypothesis that direct injection of these bone marrow derived cells can alter fibrosis and improve blood vessel formation in hearts with end stage ischemic heart disease.
Beverly Torok-Storb (Fred Hutch)
Obviously FHCRC/UW lead the world in the science and medicine applied to regenerating an hematopoietic system—a Nobel was awarded for this effort. Importantly, and less obvious is the fact that the preclinical model used to develop this application (canine model) is unique to the FHCRC/UW. We have the most extensive canine facility and experience with the canine model in the world. Now we also have canine ESC, ( I believe we have the only true lines). Hence we are posed to do critical in vivo experiments in a large, outbred, long-lived animal that has proven efficacy for translation directly to humans. Moreover developmental studies using new lines and SCNT can be done in this model now with NIH funds. Non-NIH support can focus on human ESC done in parallel. But the real bonus is that derived tissue can first be tested in dogs and if proven safe, quickly translated to patients. I strongly maintain that mice being small, inbred, and short-lived provide misleading information regarding questions of long-term regeneration by allogeneic sources of cells.
Jakob von Moltke, PhD (Immunology)
We are generally interested in the initiation of immune responses by parasitic worms and allergens, and the tissue remodeling that is a hallmark of this “type 2” inflammation. We recently discovered that type 2 immune responses in the small intestine require a specialized epithelial lineage called tuft cells. Tuft cells are normally very rare, but during type 2 inflammation the cytokine IL-13 signals in epithelial stem cells to bias their lineage commitment towards tuft cells and the mucus-secreting goblet cells, leading to dramatic changes in the cellular composition of the intestinal lining. Using genetic mouse models combined with imaging, flow cytometry, and organoid tissue culture, we are investigating the stem cell differentiation pathways that give rise to tuft and goblet cells in the intestine, with the goal of understanding how IL-13 alters cellular fate decisions.
Thomas N. Wight, PhD (Benaroya Research Institute)
This investigator leads a research program focused on the role that the extracellular matrix molecules, proteoglycans and hyaluronan, play in regulating vascular cell type and the regulation of extracellular matrix assembly. These pathways are fundamental to understanding the growth of new blood vessels in different tissues of the body, and have potential for direct tissue regeneration applications through the use of proteoglycan genes to bioengineer vascular tissue.
Alejandro Wolf-Yadlin (Genome Sciences)
The main focus of our lab is on the application of systems biology to the study of cancer. We develop proteomics tools to study cellular signaling dynamics and topology. We then apply these tools in conjunction with gene expression, epigenetic and phenotypic analyses of cellular systems to understand molecular and behavioral characteristics of cancer primary cells and cancer stem cells. The ultimate goal of our researcStemh is to identify molecular signatures of cancer progression that can illuminate potential drug targets as well as be utilized as diagnostic tools for early cancer detection.