Dr. David Scadden Exploits the Vast Potential of Stem Cells
2004 - His curiosity about how HIV is able to wreak havoc on a broad spectrum of immune cells led hematologist/oncologist Dr. David Scadden to investigate the chameleon of cells: stem cells-- unspecialized cells that renew themselves through cell division and can morph into cells with specific functions, such as insulin-producing pancreatic cells.
Dr. David Scadden"I was interested in the role of stem cells in HIV disease," says Harvard's Dr. Scadden, recipient of a 2002 Clinical Scientist Award in Translational Research, "particularly blood forming stem cells that are important in the formation of all the blood and immune elements. Since all immune elements are depressed in advanced HIV disease, I wondered if those stem cells were a target of the virus," he added. "From that, I became interested in understanding more basic mechanisms of the way stem cells are regulated, with an eye toward using those mechanisms to manipulate the stem cell for therapeutic purposes."
Dr. Scadden's research first focused on identifying the barriers that prevent stem cells from being used more broadly in a number of different diseases--not just diseases of the blood or immune system such as HIV, leukemia, and lymphoma. Three specific barriers surfaced as needing further investigation: stem cell number, cell localization, and targeted differentiation.
Stem cells are very rare cells, Dr. Scadden explains. Identifying and isolating them has been a complex undertaking, and being able to get enough of them to use clinically has been a real problem. Even in the context of bone marrow transplant, Dr. Scadden says that the number of cells needed for a human is extraordinarily high compared to the number needed in a mouse. "In humans, we need five million per kilogram for a bone marrow transplant in an adult," Dr. Scadden says. The limited number of stem cells poses problems for patients needing autologous stem cell transplantation: 10 to 20 percent of these patients don't have enough of their own stem cells to undergo the potentially life-saving procedure. And a third of patients waiting for a bone marrow donor will not find one. Umbilical cord blood, which could solve the donor problem, is not useful because the number of stem cells is too small to safely transplant into an adult.
"One of the huge hurdles to overcoming the barrier of too few stem cells is that stem cells are hard wired to be quiescent," Dr. Scadden explains. "I think the evolutionary reason is that stem cells can be quite dangerous. They could form a tumor, for example. So stem cell constraint gets imposed early on in the development of an organism and is maintained in the adult.
"In general, stem cell populations in the body are resistant to growth. They're geared to a maintenance function and not regeneration," Dr. Scadden says. "We thought if we could understand what restricts their growth, we might be able to develop strategies to increase their numbers. So we've tried to identify the brakes on cell cycling and have defined a number of cyclin dependent kinase inhibitors (CDKI)--a class of molecules abundant in primitive cells that serve as a brake on cell cycling.
Dr. Scadden and his team of researchers found that eliminating CKDIs in a mouse model increases the stem cell pool and the ability of certain tissues to repair after injury. When they tested their theory on human stem cells, they found that if they reduced the expression of one of the CDKI molecules--p21-- they could actually increase the number of stem cells. "We don't know if this discovery will ultimately be useful, but we hope that it will," Dr. Scadden says.
Dr. Scadden's approach is to examine how stem cells function in the context of complex tissue. Stem cells inhabit niches, and Dr. Scadden is examining the hematopoietic stem cells niche. "We know that blood stem cells move in the course of development to different locations and with each of those transitions in location, they have a different function," he says, adding, "it looks like location does have a big impact. We want to understand one of the components of where stem cells live that might be relevant to these changes of function."
So Dr. Scadden decided to look at bone marrow stem cells and collaborated with endocrinologists to learn about the unique aspects of bone that distinguish it from other tissues. In the process, he identified three components of bone that would be amenable to genetic modification: osteoblasts (bone-forming cells), matrix, and ionic calcium. He and his colleagues found that each of the three components has an impact on stem cells. In particular, they found that if they activated the osteoblasts, they could increase the number of stem cells. Using this discovery in a mouse model, they gave osteoblast-stimulating hormones to normal mice and then put them through a bone marrow transplant, giving them too few cells for a viable transplant. The results: the mice that received only stem cells had a 70 percent mortality rate; those that received the hormone in addition to stem cells had a zero mortality rate.
The hormone, parathyroid hormone or PTH, was approved only a year ago for treating osteoporosis. "We are initiating a human trial using PTH in the setting of bone marrow transplant for lymphoma (both Hodgkin's Disease and non-Hodgkins lymphoma)," Dr. Scadden says. "We couldn't do this without the BWF award; we're buying the drug and supporting the investigators in the clinic with BWF funding." The clinical trial is currently in the approval process.
Though he still sees patients, Dr. Scadden divides most of his time between the lab and his duties as director of the Center for Regenerative Medicine and Technology at Massachusetts General Hospital and co-director, with developmental biologist Dr. Doug Melton, of the newly inaugurated Harvard Stem Cell Institute.
For a physician-scientist so deeply involved in research and mentoring young scientists, Dr. Scadden came to his vocation circuitously: he earned a B.A. in English literature from Bucknell University and wrote a thesis on William Butler Yeats. But the stage was set early for scientific pursuits; he fondly remembers the lab his father built in the basement so he could experiment with his chemistry set and anything else he was curious about. "We basically made bombs," Dr. Scadden says with a grin. Years later, when he realized that his English degree wasn't useful in launching a career, Dr. Scadden decided he'd try medical school, based on his admiration for his family doctor. Decision became reality and Dr. Scadden acquired solid experience with clinical trials along the way. "I enjoy taking care of patients," he notes, "but I also like having a sense of both worlds that has allowed me to facilitate movement between the clinic and the lab." He also might have mentioned facilitating the career development of the trainees in his lab.