Designer blood

Every day at Children's Hospital Boston, doctors wage life-and-death battles against blood diseases -- the vicious 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 built 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 towards 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 ambitious goal, Zon and his colleague, Dr. George Q. Daley, have been drawn deeply into a fascinating and fast-moving 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, but also at least five main types of white blood cells that vigilantly prowl the body, doing battle with invaders, as well as other specialized cells. All of these cells are in constant communication so the blood can adapt as the body's needs change.

Many things can go wrong with this system, such as leukemia, when blood cells become cancerous and start growing uncontrollably, 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 -- almost miraculously -- 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 actively underway, 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 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. Critics of the work, including Governor Mitt Romney, say that it is unethical because scientists will create embryos specifically for research. Others 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.

Far from the rhetoric of Beacon Hill, the reality inside Children's Hospital is at once exhilarating and chastening. The science has been moving quickly. At the same time, Daley and the other researchers face a series of obstacles, each nothing short of daunting, and each of which could disappoint the public's rapidly rising expectations.

''I would hope to be entering the clinic in five to 10 years," said Daley, who will direct the nuclear transfer experiments. ''But that may be overly ambitious."

Bone-marrow transplants are considered one of modern medicine's great advances, but they 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 C. Guinan, a bone-marrow-transplant specialist who is associate director of the Center for Clinical and Translational Research at the Dana-Farber Cancer Institute. She said that typically somewhere between 10 percent and 30 percent suffered serious complications, 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 wouldn't just improve the odds of the transplants done today -- it could mean that many more patients could be helped.

Consider, for example, 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 a embryo whose DNA matches the boy's. From this, scientists could then extract embryonic stem cells, cells that 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.

Researchers have long been trying to achieve the same goal by using a patient's own blood stem cells, but there have been two obstacles, Daley said. It has proved very difficult to perform the kind of genetic repair on blood stem cells that can be done relatively easily on embryonic stem cells.

But the effort to carry out this elaborate procedure is fraught with obstacles. For example, only one team in the world has reported success with the first part of the procedure, in which the scientist would clone a human cell to create embryonic stem cells.

Coaxing human embryonic stem cells to become blood stem cells will be very challenging, Daley said. Today, the Daley lab can do this with mouse cells, creating a bone-marrow transplant from mouse embryonic stem cells. But sometimes the experiment fails, and he doesn't know why.

"We can go for months where the experiment works beautifully, and then go for a stretch where the mice die," Daley said. ''That is frustrating."

Even if their gambit were to work, giving every patient the option of a perfectly matched bone-marrow transplant, the operation would still be a dangerous one. The drugs used to kill the patient's original blood can have side effects, and the patient's immune system is also highly compromised. Many scientists and doctors around the country are working on other ways to improve bone-marrow transplants, said Guinan, such as improving the way drugs are used to kill the patient's original blood, and developing new strategies for counteracting common side effects.

Daley has only begun down a long path of overlapping reviews that must be finished before he can start the project to clone human cells. At Brigham and Women's Hospital, he applied in November to the institutional review board, an independent panel that ensures people participating in experiments are protected. In this application, Daley is not asking for women to donate eggs to his research, but instead will use eggs that failed to fertilize, which are regularly discarded by fertility clinics.

The hospital administration also would have to approve the research, said Dr. Barbara E. Bierer, the senior vice president for research at the Brigham. Children's Hospital and an institutional review board there also would have to approve the research. And all the Harvard-affiliated hospitals are currently negotiating with Harvard University to establish a single panel that would review all research using human embryonic stem cells.

For now, the scientists at Children's said that it has been valuable to have time to work through the many issues that the research raises, but say that they are frustrated that, in addition to all the other hurdles, the federal government has been an impediment.

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 this country, will not fund the cloning of human cells.

''If they did," Daley said, ''my lab would have started on this two years ago."

Gareth Cook can be reached at cook@globe.com.