Program Leader: Daniel G. Tenen, MD

Click here to download the HSCI Blood Diseases Program Overview.

The HSCI Blood Diseases Program was formed to maximize the local scientific expertise in the blood diseases field. The program has two main projects— one, on using the blood system to understand cellular renewal mechanisms; the other, on how to create blood cells from embryonic and other pluripotent stem cells.

The first project's research agenda is focused on identifying the molecular and cellular characteristics and pathways involved in self-renewal of hematopoietic (blood) stem cells. "Turning on" self-renewal is critical for stem cells to expand as needed for regenerating damaged tissues. Similarly "turning off" self-renewal is critical for stopping cell growth and interrupting out-of-control processes such as occur in the perpetuation of malignancy in cancer. Understanding the basis for selfrenewal and these controls is central to creating stem cell therapies.

A second, complementary project is focused on creating hematopoietic stem cells from pluripotent stem cells using multiple techniques—parthenogenetic derivation, somatic cell nuclear transfer (SCNT), and direct genebased reprogramming to produce induced pluripotent stem (iPS) cell lines. A large number of new cell lines have been created, including 12 new human embryonic stem cell (hESC) lines and dozens of iPS lines from patients with hematologic diseases and other conditions. These lines are contributing to studies of immune deficiency and several inherited bone marrow failure conditions. This work in disease-specific cell lines is now being integrated into the new iPS core facility.

Greater Than the Sum of Our Parts

In the first project, six sub-projects are under way to study mechanisms of differentiation, epigenetic traits, and niche characteristics of hematopoietic stem cells in several models, including embryonic stem cells, adult hematopoietic stem cells, and leukemia stem cells. Using different, but complementary, research tools—from zebrafish and mouse models to powerful new genomic and proteomic approaches—this collaborative group is sharing data, information, and computational tools.

All six of the sub-projects have produced multiple data sets from their experiments, and though each lab has conducted its own analysis, the data's full potential in analyzing the data sets from across labs and experiments is limited by the time and resource restrictions of each lab. Seeking to capitalize on this opportunity, the program is creating a common system to support these data sets and enable broad analysis in collaboration with bioinformatics professionals from the Harvard Initiative in Innovative Computing. The first step of collecting and aligning all existing data from the labs is under way.

The program's near-term goal is to complete and test the database using the combined data from these core labs. Once stabilized, the system will be made accessible to the larger blood diseases research community, both for contributing their own data sets to the project and for using the system to enhance their own research.

Forming the basis for a new iPS core facility at HSCI, the disease-specific iPS lines have been derived by reprogramming cells from patients with a variety of including immunodeficiency, Down Syndrome, Gaucher's disease, and Shwachman-Diamond Syndrome. Researchers are using these lines to study how gene defects influence abnormal hematopoietic development. Investigators in the Blood Program are also comparing the potential of the ESC lines to generate blood following in vitro-differentiation to that of the cohort of newly derived iPS lines.

A Model for Other Systems

Blood is arguably the best-understood mammalian organ system and has become a model for other systems in terms of the study approach, the methods employed, and the tools developed. Consequently, HSCI scientists expect that the regulators of stem cell self-renewal that are discovered in the blood system will also help researchers in other disease areas by determining if stem cells in different tissues share regulatory mechanisms. Similarly, the increased understanding of reprogramming techniques and differences among cell types will apply broadly. The disease-specific cell lines created by this project will jump-start the iPS core facility and accelerate the use of in vitrodisease-specific models. In addition to providing a deeper understanding of biological processes, this combination of tools, techniques, and model systems will help inform the design of tests and screens for compounds that control the selfrenewal process in disease, representing potential therapeutics and a potential market application prior to developing cell-based therapies.