By Gareth Cook
    The Boston Globe

    Thursday 19 May 2005

    Boston - Every day at Children's Hospital Boston, doctors wage life-and-death battles against blood diseases - the leukemias and anemias that can strike early in life.

    One of the powerful tools these doctors have is a bone marrow transplant, but many patients can't find a donor who is a close enough match to limit the risk of rejection. And even when there is a good match, the procedure is risky: The Children's program is considered one of the world's best, but 8 percent of its transplant patients died within one year, according to last year's statistics.

    Just down the block, in a steel-and-glass research building constructed by the hospital, scientists are putting together an ambitious effort to radically improve the bone marrow transplant, making it safer and available to a much larger number of patients. Their plan is to clone the skin cells of the patients themselves to create blood stem cells - a perfectly matched transplant, in theory, with virtually no risk of rejection.

    The group of researchers at Children's is one of only five academic teams in the world with plans to clone human cells, a highly controversial technique. Yet, unlike the other groups, which hope for medical applications down the road but are geared toward basic science, the team at Children's is focused on making cells to cure patients. Being at this hospital, where doctors sometimes watch helplessly as a young life slips away, makes them feel they do not have a day to waste.

    "It can be very emotional," said Dr. Leonard Zon, director of a new stem cell program at Children's. "There is a sense of urgency."

    In pursuit of this goal, Zon and his colleague, Dr. George Daley, have been drawn deeply into an area of science that is looking for a precise answer to a seemingly simple question: Where does blood come from?

    Blood is so complex that scientists refer to it as an organ, like the brain or the heart. It includes the red blood cells that carry oxygen, at least five main types of white blood cells that prowl the body, doing battle with invaders, as well as other specialized cells. Many things can go wrong with this system, such as leukemia, when blood cells become cancerous, or a long list of genetic diseases, including sickle cell anemia, where the red blood cells do not form properly.

    To do bone marrow transplants today, doctors first use a combination of drugs and radiation to kill a patient's blood system. Then they give the patient bone marrow from a donor - often a sibling - whose tissue is similar, and unlikely to be rejected by the body. In this bone marrow are a small number of blood stem cells. After they are injected into the patient, these stem cells travel to the patient's bone marrow, take up residence, and then completely rebuild the entire blood and immune systems.

    These blood stem cells, like every other cell in the body, began as a single fertilized egg cell. Using mice and tiny, striped zebrafish, scientists at Children's and elsewhere have been discovering how cells specialize as an embryo develops and trying to mimic that specialization in the laboratory.

    While these experiments are under way, the work on cloning human cells has not begun because the team does not yet have permission from the participating institutions, or from an independent board, which, by U.S. federal law, reviews all research that involves people.

    The work being planned at Children's has also been at the center of a political controversy. Some critics have charged that the destruction of any embryo amounts to the taking of a human life. Proponents have pointed to the work's potential to cure diseases, and say that an embryo is not the same as a human life. At the time the embryos are used, they are a microscopic, virtually featureless ball of about 200 cells that, if placed in a uterus, have the potential to develop into a full-term baby. Today, these same embryos are routinely destroyed as a part of fertility treatments.

    Daley and the other researchers face daunting obstacles. Bone marrow transplants have serious drawbacks. Less than a quarter of patients have a sibling with bone marrow that is closely matched. Using bone marrow from a donor that is not as closely matched dramatically increases the risks.

    For patients who survive the transplant, there can still be serious complications, said Dr. Eva Guinan, a specialist in bone marrow transplants who is associate director of the Center for Clinical and Translational Research at the Dana-Farber Cancer Institute. She said that typically 10 percent to 30 percent suffered serious problems, such as "graft versus host disease," where the new blood attacks the body, savaging the liver, skin and gastrointestinal tract.

    This leaves patients and their doctors to make a difficult calculation: Do the potential benefits of a transplant justify the risk? There are many patients today who have debilitating diseases, but not so threatening that doctors want to risk a bone marrow transplant.

    If the quest of the Children's scientists is successful, then, it would not just improve the odds of the transplants done today. It could mean that many more patients could be helped.

    Consider the case of a boy with sickle cell anemia, a potentially lethal disease in which a genetic defect causes red blood cells to form improperly. The scientists envision taking a skin cell from the boy and removing the nucleus that contains his DNA. They would then place this DNA into an egg cell, likely one donated by his mother, and then prompt this egg cell to begin dividing.

    This would be grown for several days, becoming an embryo whose DNA matches the boy's. From this, scientists could then extract embryonic stem cells, which can become any cell - including blood - in the body.

    With this done, the scientists would correct the stem cells' DNA, using a proven laboratory procedure to change the portion that causes sickle cell anemia. Then, in a much more difficult step, they would coax the embryonic stem cells to become blood stem cells, providing an almost perfectly matched bone marrow transplant.

    A room near one of Daley's labs is waiting to be renovated, with a set of high-tech tools used to do cloning sitting in a box. The federal government, which pays for most scientific research in the United States, will not fund the cloning of human cells. "If they did," Daley said, "my lab would have started on this two years ago."