SISTER, SAVIOR

Children’s Immunology chief Raif Geha, MD, and gastroenterologist Samuel Nurko, MD, MPH, struggled to bring Andy’s infections under control. Meanwhile, Jordan Orange, MD, PhD, an immuno-genetics specialist, searched for clues to Andy’s condition. Orange was conducting research on the immune system’s master switch, the gene NF-kB Essential Modulator, or NEMO. Nine months after the Treviños’ arrival, Orange discovered Andy’s problem: a rare NEMO mutation, affecting only boys, was suppressing his immune-response signal. Andy’s immune cells, like an army deprived of ammunition, couldn’t fire a single defending shot against infection.

The only hope for a cure was risky–chemotherapy to destroy Andy’s faulty immune system, followed by a transplant of healthy blood stem cells from bone marrow or umbilical cord blood to restore it. Success depended on a genetically matched donor. The Treviños searched donor registries for two years without success. Andy’s best chance would be a sibling–specifically, a girl who might

Andrés and Paulina Treviño arrived at Children’s Hospital Boston in September 2000, with two suitcases and their desperately sick 16-month-old, Andy. He had suffered continual, life-threatening infections since birth, but no one knew why. After consulting 70 doctors and spending 375 days in the hospital in their native Mexico, the Treviños had run out of options.

Conceiving this sibling involved the most advanced diagnostics and experimental genetic technology available–sperm sorting to ensure a girl, cell testing for a genetic match, in-vitro fertilization (IVF), and pre-implantation diagnosis. But the Treviños’ decision was simple. “We’d always wanted two or three children,” says Andrés. “Once we knew having another child could help save Andy, we had no hesitation.” After repeated IVF attempts,Paulina became pregnant. In March 2004, the Treviños welcomed Sofia, a red-cheeked, curly-haired beauty. Andy, then 5, was enthralled with his baby sister.

Later that year, in germ-free isolation at Children’s, Andy endured 10 days of immune-destroying chemotherapy. Then he received a transfusion of Sofia’s blood stem cells, saved and stored from her umbilical cord. Over several months, healthy, normal cells regenerated Andy’s immune system. With Sofia’s gift, Andy was cured.

No child should die because a bone marrow donor can’t be found, yet many do. A determination to save these patients, and many more of all ages, drives the Children’s Stem Cell Program, led by director Leonard Zon, MD, and associate director George Daley, MD, PhD. Laboratory-grown embryonic stem cells (ESCs) may one day provide the ideal treatment for patients like Andy. With their potential to form not just blood, but any tissue in the body, they may become a limitless medical repair kit. New, healthy cells will take over for cells damaged by diseases like sickle-cell anemia or leukemia and restore normal function rather than simply treating symptoms. Conditions such as Parkinson’s or diabetes that require life-long medication will be treated instead with cell implants. Stem cell science promises to restore health for millions suffering and dying from currently incurable conditions.

Children’s Stem Cell Task Force, a group of business and philanthropic leaders, worked with Zon and Daley to develop a strategic plan for delivering cell-based therapies to the clinic in as few as seven years. There are good reasons the plan’s initial target–blood diseases including leukemias, severe anemias, and immune deficiency disorders–is the most efficient way to prove cell therapy works. Bone marrow transplantation, the technique for delivering blood cells that saved Andy Treviño, is well established and effective. (Similar delivery mechanisms don’t yet exist for getting most other cell types efficiently and safely to their targets.)

Zon and Daley are renowned blood and cancer specialists as well as internationally recognized leaders in stem cell research. Both are Howard Hughes Medical Investigators (HHMI), one of the most competitive, prestigious, and coveted recognitions in biomedical research. In addition, the Stem Cell Program is one of just a handful worldwide developing somatic cell nuclear transfer (SCNT).

To speed the science towards cell therapy clinical trials, the program is focused on four key goals:

• Creating rejection-proof cells: SCNT is a leading technique that makes it possible to create healthy cells the patient’s body won’t reject. Therapeutic cells are created by inserting the nucleus from a regular cell (e.g., skin) into an egg whose own nucleus has been removed, and coaxing it to develop ESCs. Daley was the first to show, in mice, that the new cells, with their gene defects corrected, can be implanted to cure disease–no donor and no rejection involved. His lab is translating SCNT techniques developed in animals to human cells.

• Growing needed tissues: ESCs are so valuable because they’re capable of differentiating into any type of cell. The Stem Cell Program has already differentiated human ESCs into blood cells–the next goal is to capture the precursor blood stem cells needed for therapies, as it has been done in mice.

• Modeling disease and devising cell markers: Along the way, Stem Cell Program researchers need to track success. They’ll develop biomarkers–biochemical signatures that can be used to measure the progress of disease or the effects of treatment–for blood stem cells.

• Translating findings into treatments: Bringing clinical-grade cells into production quickly and safely is critical to developing treatments. One of the most immediate needs is to buy access to an existing facility nearby where new cell lines can be derived under sterile conditions satisfying the Food and Drug Administration’s requirements.

Several stunning developments this year demonstrate the Stem Cell Program’s progress toward its primary target, blood disease. Along the way, its innovative approaches have uncovered important findings for other diseases like cancer and heart disease.

• Existing human stem cells lines available for research are limited. Using discarded IVF embryos–considered medical waste–Daley recently generated 12 new viable hESC lines.

• While perfecting these techniques, Daley also has isolated mouse ESCs from a parthenote–an egg that’s been stimulated to start developing without fertilization. A parthenote can’t fully develop into a fetus but is a rich source of ESCs. The egg and resulting ESCs have the same genes, making the cells ideal for rejection-proof transplant back to the egg donor.

• The Zon lab is aggressively investigating genes and chemicals that can transform hESCs into the vast quantities of blood stem cells needed for transplant. Zon recently found a drug, prostaglandin E2, that stimulates ESCs to differentiate into blood stem cells. It also boosts blood stem cell production by 300%–the best results ever reported. This finding has immediate benefits–the drug could accelerate recovery for patients who’ve had bone marrow transplants. Clinical trials may begin within a year.

 • Investigators recently coaxed a beating contractile heart muscle cell from a human stem cell. The hope is that one day such cells will be used to repair damaged heart muscle.

• Stem Cell Program researcher Carla Kim, PhD, was the first to discover lung stem cells and is studying the link between the lung stem cells and lung cancer.

These recent breakthroughs are exhilarating. But delivering on their potential involves hard bottom-line reality.

Bringing blood disease cell therapies to clinical trials will require $50 million. Each subsequent disease target will need an estimated $16 to $20 million. Since federal policy currently prohibits funding for all but a very limited number of stem cell lines, other resources must be used for the rest of stem cell research. Philanthropic support is critical.

Generous donors have given more than $20 million toward our goal, but much more is needed for Children’s Hospital Boston to usher in a new era of medical care “We’re at a turning point,” says Jonathan Kraft, who, with his wife, Patti, co-chairs the Stem Cell Task Force. “We’re looking at the greatest, most immediate impact on the lives of sick and suffering patients, at vastly reduced financial and human costs.

This is the place to invest. There’s no time to lose.”