Molecular Hematopoiesis

Our research interests span basic laboratory studies through pioneering clinical trials focusing on stem cell biology and hematopoiesis—the development and differentiation of bone marrow stem cells into multiple types of blood cells. Hematopoiesis occurs throughout life, and dysfunction of these processes can result in bone marrow failure or leukemia. We utilize cutting edge molecular technologies such as genetic barcoding and single cell gene expression analyses to understand the “family tree” linking stem cells to their daughter cells and eventually to mature circulating blood cells, in both health and disease. For over thirty years, our research group has utilized the rhesus macaque transplantation model to study hematopoiesis and the immune system. This model provides unique predictive insights into human hematopoiesis and blood diseases. Our studies have provided insights into stem cell frequency, lifespan, aging, geographic location, and differentiation. Recently we provided the first direct evidence for self-renewal and long-term persistence of mature natural killer cells, explaining aspects of natural killer cell memory and providing insights into dynamics of these cells following infections or as therapies to fight cancer.

We have also been engaged in more than three decades of efforts to design, optimize and utilize methods to genetically modify or correct hematopoietic stem cells, with direct translation to human gene therapies. We have focused on understanding and improving the safety and effectiveness of a variety of gene transfer vectors that integrate into the genome of hematopoietic stem cells. The rhesus macaque model has been of great utility for assessment of the safety and efficacy of novel gene and cell therapies. These translational studies have provided critical information to improve clinical gene therapies targeting blood diseases such as inherited immunodeficiencies and sickle cell anemia. We have also investigated gene editing technologies, such as CRISPR/Cas9, to correct or modify the genome at specific gene targets, creating macaque models of human hematopoietic stem cell aging and marrow failure disorders, and using gene editing to overcome potential toxicities of CAR-T cells directed against forms of leukemia.

We have expanded our focus to other types of stem cells, particularly induced pluripotent stem cells (iPSC). We were the first to derive rhesus macaque iPSC and have gone on to use the rhesus iPSC model to develop safe and effective approaches for tissue and organ regeneration, particularly focused on the heart, and on methodologies to track cells in vivo long-term following administration, crucial information for optimizing safety and efficacy of clinical cell therapy products.

Clinically, we have led the clinical development of approaches to stimulate human hematopoietic stem cells in vivo, most notably in patients with severe refractory aplastic anemia. The small molecule oral drug eltrombopag was found to improve blood counts in patients with this condition, in a trial led by Dr Dunbar at the NIH Clinical Center together with other NHLBI investigators. This resulted in the first FDA approval for new drug to treat aplastic anemia in over 30 years. Ongoing clinical trials focus on testing the utility of this drug in other bone marrow failure syndromes.