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There’s a new celebrity in town. Like any famous star, this one is alternately praised and maligned in the popular press. Open a newspaper, flip on a television or peruse a magazine and you’ll likely be inundated with news and views about this latest luminary—the mighty but microscopic stem cell. What is a stem cell? Why all the hubbub about a cell, and why should researchers from St. Jude Children’s Research Hospital study it? Mary Jo Menzel knows exactly why stem cells are important—because these lowly cells may have the ability to transform her son’s life.
An accomplished swimmer and enthusiastic soccer player, Jacob Menzel is gifted with a nimble mind and incisive analytical skills. He excels at mathematics, puzzles and computer games. Like other boys, Jacob spends hours in imaginative play, adroitly fashioning Lego creations and pondering the nuances of Pokemon and Harry Potter. But this bright boy is far from typical. He is one of a handful of children on the planet to undergo stem cell infusions for osteogenesis imperfecta (OI), a cruel genetic disorder also called “brittle bone disease.”
Jacob’s journey began October 20, 1994, when the obstetrician heard bones breaking as she pulled him from the womb. “In the first few years of his life, Jacob broke a bone, on average, every month,” says his mother. OI affects the production of collagen in Jacob’s body. In addition to frequent bone fractures, the disorder leads to excessive fragility, short stature and deformities, and in its severe form, death. Until recently, children like Jacob faced a grim future.
But in 1996, a glimmer of hope appeared when Ed Horwitz, MD, PhD, of the St. Jude Hematology-Oncology department performed the world’s first bone marrow transplant for osteogenesis imperfecta. Since then, Horwitz’s use of stem cells has made headlines as the public clamors for information about the controversial cells.
What are stem cells?
In the past few years, stem cells have generated great excitement among researchers, physicians, patients, the media and the general public. These rare and powerfully therapeutic cells are immature “master” cells that can renew themselves and develop into a variety of cell types. Most stem cells occur in the bone marrow, although they have been identified in other organs, as well. Marrow stem cells produce all of the body’s oxygen-carrying red blood cells, infection-fighting white cells and the platelets necessary for clotting.
For many years, doctors at St. Jude have been performing bone marrow transplants. When the “sick” bone marrow is replaced with donor marrow, patients’ bodies begin to produce new, healthy cells. Only in the past decade have scientists been able to isolate individual stem cells from the blood and bone marrow for use in transplants. Bone marrow contains stem cells, but it also contains other kinds of cells that may not benefit patients. As stem cell purification methods have become more accurate, the number of bone marrow transplants has declined, and the number of stem cell transplants has increased. At St. Jude, about 150 stem cell infusions are performed each year.
Stem cell use at St. Jude
Some scientists at other institutions have obtained stem cells from human embryos. This highly controversial source of cells has not been used at St. Jude. Stem cells used for transplantation at the hospital are harvested solely from the blood or bone marrow of children or adults.
Malignant diseases treated with stem cell transplantation at St. Jude include leukemias, brain tumors, Hodgkin disease, non-Hodgkin lymphoma, neuroblastoma, Ewing sarcoma and other relapsed solid tumors. Non-malignant disorders include sickle cell disease, severe combined immunodeficiency syndrome, Fanconi anemia, Wiskott-Aldrich syndrome, thalassemia, aplastic anemia and metabolic storage disorders. Stem cell transplantation offers many patients their last and only chance for a cure. This treatment method is often used for children whose diseases have not responded well to conventional therapy or whose diseases have returned after therapy.
In some treatment plans, patients serve as their own stem cell donors. In these cases, stem cells are harvested from the patients. The children then undergo chemotherapy and perhaps radiation, which destroy the immune system along with any cancerous cells. When the previously stored stem cells are infused, they begin producing new cells. Until the immune system fully recovers, the child is highly susceptible to infection.
An allogeneic transplant occurs when another individual donates stem cells for the patient. This process is extremely complex, because the patient’s immune system is replaced by that of another person.
St. Jude clinicians attempt to find a donor whose tissue type, or human leucocyte antigen (HLA) type, matches the patient’s. The closer the match, the lower the risk to the patient. If a patient has four siblings, the odds are that one of them would be a perfect match, possessing all six of the antigens necessary for successful engraftment. If the patient does not have an HLA-identical sibling, then St. Jude staff members search for a matched unrelated donor. Because of recent scientific advances, some parents may now be considered as donors, even though they match only three of the six antigens. In an allogeneic transplant, clinicians must ensure that the patient’s immune system does not perceive the donor’s stem cells as foreign and destroy them. Another serious complication is graft-versus-host disease. If the donor’s stem cells are not purged of infection-fighting T-cells before the transplant, those cells will mount an attack against the patient or the host.
In St. Jude laboratories, researchers and clinicians are working feverishly to harness the power of stem cells. One St. Jude project has the potential to revolutionize transplantation of these cells. About half of the children who need transplants do not have matched sibling or unrelated donors. That number is much higher for ethnic minorities, who are underrepresented in the marrow registry. Until recently, those children had no chance for a cure. But a team led by Rupert Handgretinger, MD, director of Stem Cell Transplantation at St. Jude, has begun transplanting stem cells from some parental donors. A protocol, or scientific treatment plan, for this procedure has been developed.
Because a parent only shares half of the antigens necessary for a child’s transplant, Handgretinger and his staff must take extraordinary measures to prepare both patient and donor cells for transplantation. By using a new procedure called magnetic activated cell sorting, St. Jude staff can magnetize and isolate donor stem cells, reducing the chance that donor T-cells will attack the patient, or host, and cause graft-versus-host disease.
“We developed a method whereby we can process billions and billions of cells and pick out only the stem cells, leaving the rest behind,” says Handgretinger. Staff members closely monitor chemotherapy and/or radiotherapy usage to eradicate cancer cells with the fewest possible side effects. Handgretinger is excited that St. Jude staff may soon be able to use parental donors on a regular basis for stem cell transplantation. “You’ll never find a more motivated donor than the mom or dad of the patient,” he says. “And you have the donor sitting at the patient bedside every day. If you need a second transplantation, you don’t have to do a donor search, because it’s easy to find that donor.”
Handgretinger and his colleagues are continually conducting research to better understand the biology of stem cell transplantation, to improve the processes and to make the procedures safer. “We can never stop doing this kind of research until we improve the survival rates to 100 percent,” Handgretinger asserts.
Another St. Jude “first”
In another St. Jude laboratory, researchers led by Brian Sorrentino, MD, director of Experimental Hematology, have discovered what they believe to be the world’s first “universal” stem cell marker. The team found that expression of a gene called ABCG2/Bcrp1 allows scientists to identify stem cells from a variety of sources. The gene provides scientists with a much more accurate way of identifying true stem cells than has been available in the past. Stem cells in the bone marrow, skeletal muscle and the early mouse embryo expressed the ABCG2/Bcrp1 gene in a highly specific manner; most mature cells showed no expression, underscoring the gene’s potential use as a stem cell marker.
Scientists have long been seeking a good way to identify stem cells. In a sample of 100,000 bone marrow cells, only a few may be stem cells. Scientists have been using several methods to identify the cells, including a common stem cell marker called CD34, but most cells identified with this method are not true stem cells. “People have looked at a variety of other markers. Nobody has ever found an absolutely specific stem cell marker,” says Sorrentino. “Our work suggests that ABCG2/Bcrp1 could be that type of marker.”
Expression of the ABCG2/Bcrp1 gene may also ensure that stem cells remain in a primitive state—that they do not differentiate into red blood cells, white blood cells or other kinds of cells. This discovery might help scientists control stem cell differentiation. The St. Jude research involved laboratory animal stem cells. Sorrentino and his team are currently working on a way to use the marker to identify stem cells from human bone marrow. The scientists are also involved in research that will allow stem cells to be used as gene therapy vehicles. Some diseases are caused by defective genes. If a stem cell containing a normal copy of a gene is put into a patient, that cell could theoretically produce billions of normal cells for the rest of the patient’s life.
A childhood cancer survivor himself, Sorrentino says he always knew he wanted to become a physician-scientist. A battle with Hodgkin disease at the age of 17 cemented that goal. Sorrentino’s work with stem cells may help untold thousands of children with immune system disorders, genetic diseases, Hodgkin disease and other kinds of cancer. “St. Jude is a great environment for doing research and working on blood,” says Sorrentino, who came to Memphis from the National Institutes of Health in 1993. “We’ve got the world’s leading experts in blood here. I’ve heard it said that the only thing that will limit you at St. Jude is your ideas, and that’s the way I feel. It’s a great place to do science and to do medicine.”
New life for brittle bones
Jacob Menzel’s mother says that St. Jude is also a great place to come for a healthy dose of hope. In the summer of 1997, Jacob received the world’s third bone marrow transplant for osteogenesis imperfecta. Horwitz infused the boy with whole bone marrow, which contains mesenchymal stem cells that are capable of making bone and connective tissue. Sure enough Jacob’s bones began to grow.
A year earlier, Horwitz had performed the world’s first stem cell transplant for osteogenesis imperfecta. The mesenchymal stem cells had engrafted and differentiated into bone cells. The cells actually altered the structure of the bone and helped the bones grow more normally, but eventually the growth began to slow down. Horwitz then established a new protocol, in which mesenchymal stem cells were removed from donor bone marrow and infused into patients. Again, the cells began to produce new, healthy bone cells, which strengthened the bones and made them grow. Jacob received stem cell infusions during this study.
“The stem cell infusions most definitely helped,” says Mary Jo Menzel. “The science just makes sense: you introduce cells into somebody’s body, and the body accepts those cells.”
But eventually the benefits again began to taper. Soon, Horwitz, will embark on a third stem cell protocol aimed at further reducing the effects of the disease.
“We’d love to be able to give them one treatment and have them cured,” says Horwitz. “But we’re not there yet. Rarely in medicine do you hit a home run. Most advances are made in incremental fashion, a little bit at a time. Think about leukemia. Until 1948, the cure rate was zero. By 1962, it was 4 percent. By 2001, it’s up to about 80 percent. But that didn’t happen in a year. It happened in 40 years. In the past five years, we’ve had extremely positive outcomes. We’ve proven that this can work, it’s safe, and it seems to be beneficial. We’re going to build on that.”
While Horwitz works on ways to help Jacob, the boy concentrates on making friends, attending classes and pursuing busy social lives. An elementary school student in Wisconsin, Jacob enjoys a popularity that astounds his mother. “I’m famous at school,” he says, matter-of-factly, when strangers recognize and greet him in public places. Although Jacob still uses wheelchairs, he makes the most of it, playing wheelchair soccer.
Reprinted from Promise magazine, winter 2002