Treating Patients

Blood Diseases: The First Frontier in Stem Cell ResearchXiao Guan, PhD, postdoctoral research fellow in the hESC Core, removes frozen stem cell samples from a liquid nitrogen storage tank.

Hematologist George Q. Daley, MD, PhD has seen children with blood diseases die, not just from the ravages of their disease, but also because they aren’t candidates for bone marrow transplants, which are currently the best tool for treating many of these diseases. The driving force behind his work is to employ stem cells to create safer, genetically matched bone-marrow transplants for patients. Daley’s son, when asked in kindergarten what his father did, summed it up well: “My dad looks into microscopes at stem cells to help people live.”

Daley, Principal Investigator in the Stem Cell transplantation Program at Children’s Hospital Boston, has seen bone marrow transplants save lives. If a closely matched donor can be found, an infusion of healthy blood stem cells from that donor can bring a remission to patients with leukemia, lymphoma, and various genetic blood diseases. But many patients aren’t so lucky, and their closest bone marrow match is from donors outside their family. For them, bone marrow transplant is a heroic, toxic therapy that can claim the lives of up to 20 percent of patients in the first year—an exceptionally high mortality rate for a routine medical procedure.

Daley began his career in the 1980s by seeking an alternative to bone marrow transplants for chronic myeloid leukemia (CML). He showed the cause of CML to be an oncogene known as Bcr-Abl, a finding that helped pave the way for the highly successful “designer” chemotherapy drug, Gleevec, which blocks Bcr-Abl’s errant growth signals and puts more than 95 percent of CML patients into a lasting remission. His lab went on to identify genetic mutations in Bcr-Abl that enable CML to become resistant to Gleevec, and today, his research group is seeking drugs that target these mutations.

But as far back as 20 years ago, Daley was thinking about another solution: embryonic stem cell. While working in the lab of Nobel laureate David Baltimore, PhD, Daley began trying to coax mouse embryonic stem cells to become blood cells, thinking, “if you could make blood stem cells from embryonic stem cells, you would have a universal donor cell for bone marrow transplant.”

Daley interrupted these studies to complete clinical training in hematology and bone marrow transplantation, but returned years later to attack this problem in his own lab. He has devoted the last 15 years to proving the potential of embryonic stem cells in treating disease.

With Rudolf Jaenisch, MD, at the Whitehead Institute, Daley made embryonic stem cells from mice with a genetic blood disease causing a severe immune deficiency. They used gene therapy to fix the genetic defect, then got these corrected cells to make blood stem cells that matched the mice genetically. As reported in the journal Cell in 2002, the blood stem cells, injected into the mice, built a new, healthy blood system and repaired the animals’ immune disease.

Recently Daley developed a new protocol to add 5-7 genes that reprogram a iPSC to a cell with good transplantation effect. This work is moving to clinical translation. We would culture one of the patient’s cells, generate stem cells compatible with their immune system, correct the gene mutation causing their disease, and then create healthy replacement tissues.

“We have very high hopes of being able to treat patients with the products of stem cells, and we’re hopeful that one of the first successes will be for diseases of the blood,” says Daley. “I see kids with sickle cell anemia, a painful disease where a single abnormal gene causes their blood to become thick and sludge in their vessels. If we could make stem cells from these children, repair the sickle-gene defect, and make blood stem cells for transplant—as we’ve done in a mouse model—we could offer these children a potentially curative therapy.”

The same approach could be used to treat any one of a large number of blood diseases, Daley says, and the longer-term goal is to move to other kinds of diseases, ranging from cystic fibrosis to metabolic disease to heart disease.

To get there, Daley and his lab are seeking to create and study embryonic and other types of pluripotent stem cells for research purposes using all possible techniques. His lab has made groundbreaking advances in developing cells that are much like human embryonic stem cells, by genetically reprogramming ordinary skin cells — even, in the early days, volunteering himself for a skin biopsy. Daley’s team has also created mouse embryonic stem cells from eggs alone.

Leaving no option unexplored, Daley’s lab has also produced over a dozen lines of human embryonic stem cells since 2006, using surplus embryos donated by couples undergoing in vitro fertilization (IVF). Eleven of his lines were among the first 13 to be deemed eligible for U.S. government research funding under new guidelines announced by the Obama administration in March, 2009.

In his quest for less toxic treatments for his patients, Daley has become a prominent voice in the public debate about stem cell research. He was elected president of the International Society for Stem Cell Research (ISSCR), serving from 2007–2008, and headed the ISSCR committee that published international guidelines for the ethical and responsible conduct of research with stem cells. In Congressional testimony, he has challenged lawmakers to weigh the desire to preserve a frozen embryo made through IVF against the needs of children with life-threatening diseases. Dr. Daley recently authored the updated guidelines for clinical use of stem cells.

“As a physician and as a scientist and as a father I live in a practical world of choices, and a world in which disease is a grim reality,” he told the Senate Appropriations Subcommittee on Labor, Health and Human Services, Education in 2005. “Unless we want to turn back the clock, and outlaw in vitro fertilization, then we as a society have already accepted that many more embryos are created than will ever become children. I feel it is morally justified to derive benefit from these embryos through medical research instead of relegating them to medical waste.”

Since its early success using embryonic stem cells to treat immune deficiency in a mouse model, Daley’s lab has gone on to explore stem cell treatments for hemoglobin disorders like thalassemia and sickle cell anemia. Work continues apace with both induced pluripotent cells (iPS cells) and embryonic stem cells.

Recently, using iPS technology, Daley’s lab learned new and unexpected things about another condition called dyskeratosis congenita, a severe blood disorder that causes premature aging—revealing much about the biology of stem cells, aging, and cancer in the process. And, using embryonic stem cells, Daley and colleagues were able to model Fanconi anemia, which scientists have been unable to model in mice. They showed that the genetic defect causing the disease impairs blood formation from the earliest stages of embryonic development.

Drs. Daley and Zon developed a new set of iPSC lines from patients with Diamond Blackfan anemia. This rare disease has no direct treatment. Using the iPSC lines, Dr. Daley create blood progenitors and used these to screen for a small molecule to treat the disease in a dish. The work shows a drug SMER28 that could be directed to a clinical trial.

“Stem cells have so much to offer our basic understanding of disease processes, and this work yielding fruit today,” says Daley. “But they also offer so much promise for future therapy, which is our major goal.”