Cell Biology, Developmental Biology
Boston Children's Hospital
Dr. Daley is also Samuel E. Lux IV Professor of Hematology and Director of the Stem Cell Transplantation Program at Boston Children's Hospital and a professor of biological chemistry and molecular pharmacology and of pediatrics at Harvard Medical School.
Stem Cells in Development and Disease
Like a movie with multiple plots spiraling around an intriguing lead character, George Daley's scientific career centers on a major player in human biology—the cell that creates the entire array of blood cells.
The hematopoietic stem cell (HSC), which gives rise to the progenitors of all the differentiated, specialized blood cells, is at center stage in Daley's laboratory. Research in his lab and others has shown that the HSCs can have both positive and negative influences on the course of some diseases.
In some of his earliest research, Daley showed that an oncogene known as Bcr-Abl, which spurs malignant growth of HSCs and overproliferation of white blood cells, is responsible for chronic myelogenous leukemia (CML). Bcr-Abl is created when two normal chromosomes inappropriately swap genetic material. The highly successful drug Gleevec (imatinib) can restore the normal ratios of blood cells by blocking Bcr-Abl's errant growth signals, but many patients become resistant to the drug when new mutations arise.
In more recent studies, Daley and his colleagues identified many of the changes that confer resistance to Gleevec. Now, his research group is devising methods to detect these mutations and is evaluating drugs that target them. Of special interest, Daley says, is a “mutation from hell” that makes relapses in CML patients very difficult to treat.
Although the master blood stem cell is at the heart of CML, the regenerative power of even more versatile stem cells underlies some of the most exciting prospects in biomedicine—correction of genetic disease and the potential to regenerate healthy tissue to repair damage in the brain, heart, pancreas, and other organs.
What Daley has learned about how Bcr-Abl sends blood stem cells down a cancerous path was crucial to understanding how normal HSCs are generated from the true master cells of the body—embryonic stem cells. “Back in 1990, when I was in David Baltimore's laboratory at the Whitehead Institute, I began treating mouse embryonic stem cells with different kinds of serum and getting them to become blood cells in a Petri dish,” Daley recounts. “Even then I was thinking that if you could make the complete hematopoietic lineage, you would have a universal donor cell for bone marrow transplantation.”
Thus far, Daley and his colleagues have been able to make blood stem cells that will regenerate a new blood-forming system in mice—a step toward a universal marrow transplant source—but not without certain genetic manipulations. “We're still missing some of the key elements of the differentiation program that would allow us to understand how embryonic stem cells produce HSCs,” he says.
While continuing to study these questions, Daley has always kept his eyes on the bigger goal of reprogramming adult tissue cells from an individual patient so they revert to an embryonic state. Once in this more primitive state, the adult cells can theoretically be coaxed into developing as healthy replacement tissues.
Daley and others are refining and testing several approaches to make reprogramming more efficient. One approach relies on a technique called nuclear transfer, in which the nucleus of an adult cell from a mouse with a genetic blood disease is placed into a hollowed-out human egg cell containing natural factors that reprogram the nucleus, creating a new embryo. Embryonic stem cells removed from the embryo are then grown in culture, where the genetic flaw is repaired. Researchers can then direct the cultured stem cells, by chemical and other means, to produce HSCs that can regenerate a healthy blood system in the mouse, curing the disorder. The Daley group has accomplished this with a genetic immune disease in mice, but so far the process is extremely inefficient.
Another powerful technique, parthenogenesis, does not require a donor nucleus. Eggs, or oocytes, are artificially stimulated to duplicate their chromosomes, resulting in an embryo for cell regeneration therapy that can be tailored to be immunologically compatible with any recipient. Daley ultimately envisions “banks” of master cells and tissues for matching to specific patients, but the transplantation work is currently in a basic modeling stage in animals, he says.
A third strategy under investigation in Daley's lab involves nuclear transfer using animal instead of human oocytes to get around the shortage of human eggs.
In parallel with his research, Daley has been an articulate and authoritative voice in the public discussion of stem cell research and its future prospects. He is often invited to speak at public forums and has testified before Congress in support of fewer governmental restrictions on research with human embryonic stem cells. He was elected president of the International Society for Stem Cell Research (ISSCR) for 2007–2008 and headed the ISSCR committee that published international guidelines for the ethical and responsible conduct of research with stem cells.
Because of restrictions on federal funding of research on embryonic stem cells derived from cell lines not approved by the Bush administration, “we remain excessively constrained in the United States in the kinds of questions we can ask,” says Daley, who receives some private research support from the Harvard Stem Cell Institute and Children's Hospital. “It is tremendously exciting that the HHMI funding will give me greater flexibility to do research on `nonpresidential' cell lines and take it in a direction that won't be as limited.”