Hemophilia, a rare bleeding disorder, stems from a single inherited mutation in any of several genes required for blood to clot properly. Katherine High has dedicated her career to unraveling the molecular basis of hemophilia, and she has been at the forefront of a movement to develop gene therapy as a treatment for the disease. High and her colleagues have developed models of hemophilia in mice and have worked with dogs in which hemophilia occurs naturally. They have demonstrated that they can successfully treat the disease in mice and dogs by inserting a normal clotting factor gene into the animals. She is now focused on adapting this therapy for humans.

High majored in chemistry as an undergraduate and chose to pursue a medical degree—rather than a Ph.D. in chemistry, as originally planned—after spending a year working alongside researchers investigating the root causes of atherosclerosis. As a medical student, she was discouraged by the emphasis on memorizing facts and took a year off to do chemistry research—almost deciding to drop out of medical school altogether to get her Ph.D. The chemistry professor in whose lab she was working encouraged her to finish medical school and then pursue postgraduate studies in chemistry, if she still desired. But when High returned to medical school, "it suddenly all made sense to me, and I decided to stay in medicine."

Although High abandoned the idea of a Ph.D., her work regularly crosses the boundaries between the bench and the bedside, as she prefers to spend her time doing laboratory research of direct relevance to treating patients. "If you have a firm grounding in the science, you can approach clinical problems clearly," High believes. She was drawn to hematology because, "of all medical specialties, it is perhaps the best understood at the molecular level," one that matches her interest in chemistry, biochemistry, and molecules.

In 1984, as High was completing a hematology fellowship at Yale, scientists cloned the genes for the two clotting factors associated with virtually all forms of hemophilia, a feat that presented High with an opportunity to sort out the molecular basis of the disease. Initially she focused on defining mutations in these clotting factor genes that result in hemophilia. This line of research has enabled High and others to pinpoint carriers of this disease and offer prenatal counseling to women who carry a mutation for the disease. It has also allowed her to analyze the relationship of the structure of the clotting factor molecules and their function. Because some new therapies only work with certain mutations, this knowledge will be critical.

High's attempts at gene therapy have focused primarily on hemophilia B, the less common form of the disease, which affects about 3,000 men and boys in the United States. In general, hemophilia affects only males because the clotting factor genes are carried on the X chromosome. Hemophilia B is caused by one of several possible mutations in the gene for factor IX, an agent that is part of a cascade of proteins involved in blood clotting. Without enough factor IX, people with hemophilia can experience uncontrollable bleeding, including spontaneous and life-threatening bleeding into the joints or the central nervous system. In severe cases, patients must undergo a lifetime of clotting factor infusions to control bleeding.

High has demonstrated in dogs with hemophilia B the principle that gene therapy can be effective in treating the disorder. Dogs that received a single injection of the gene for factor IX produced the clotting factor for more than five years, her research shows. Human trials have proved more challenging, however. In small clinical trials using an adeno-associated virus that High developed to ferry the correct form of the factor IX gene into patients' cells, a few patients produced therapeutic levels of clotting protein, but for only a few weeks. One major problem, High believes, is that the immune system is attacking the virus that delivers the gene. She is now exploring ways to modulate a patient's immune response just long enough for the virus to deliver the gene safely to the patient's cells. Despite hurdles, High remains optimistic about the prospect of gene therapy for hemophilia: "There is no question that gene therapy ultimately will succeed. We have to walk before we can run. But we're going to get there."