In 1976, my final year of medical school, I travelled abroad and spent several months working in the hematology clinic at Hadassah Hospital, in Jerusalem. Every day, I attended to children and teen-agers suffering from a blood disorder called beta thalassemia. They were easy to identify in the clinic waiting room. Their skin was a pale yellow, their skull and facial bones were distorted, and their abdomens bulged from an enlarged liver and spleen. Many were short of breath, with swollen legs and other signs of heart failure. Beta thalassemia, like its better-known cousin sickle-cell disease, is caused by a congenital defect in the globin protein, a key component of hemoglobin, the substance that allows our red blood cells to carry oxygen. Children who inherit only one copy of the faulty gene from their parents usually experience no symptoms; those who inherit two can suffer the full-blown effects of the disorder. Their red cells break down, resulting in severe anemia.

View more

Beta thalassemia is one of the most common genetic diseases in the world, affecting an estimated three hundred thousand people, with another sixty thousand born every year. (Evolutionary biologists speculate that the gene has survived for so long because, like the sickle-cell mutation, it may confer resistance to malaria.) Beta thalassemia is prevalent in Africa, Asia, the Middle East, and, especially, the Mediterranean. Its name comes from the Greek words thalassa, meaning “sea,” and haema, meaning “blood.” In many countries, including England, Greece, Iran, Saudi Arabia, and Taiwan, couples are screened for the disorder before they conceive, so that they know the chances of their child inheriting it. Once a patient shows symptoms of beta thalassemia, treatment is essentially palliative, consisting of regular transfusions of red blood cells from healthy donors. But with these life-saving transfusions come large amounts of iron, which builds up in the liver, heart, and other organs, amplifying the damage of the disease itself. At Hadassah, few of the patients with the severe form of beta thalassemia lived into adulthood. The years before death were typically marked by broken bones, recurrent infections, and overwhelming fatigue.

Now, a little more than four decades after I cared for these young patients, science is on the cusp of curing the disease. This week, the New England Journal of Medicine published a landmark paper on beta thalassemia by researchers in the United States, France, Australia, and Thailand. Twenty-two patients with the condition, treated at six centers around the world, underwent so-called gene therapy, a process in which the normal variant of a gene is inserted into the patient’s DNA, compensating for the abnormal one. In this case, the researchers retrieved immature stem cells from each patient’s bone marrow—the body’s blood factory—and isolated them in the laboratory. Next, they used an otherwise harmless virus to infect the cells with a copy of the normal globin gene. They cleared the patient’s marrow of diseased cells using chemotherapy, then reintroduced the genetically altered cells into the bloodstream—what is known as an autologous transplant. The cells found their own way back into the marrow.

The researchers’ hope was that the modified stem cells would mature into red blood cells and produce robust amounts of healthy hemoglobin. That hope was realized. Nine of the twenty-two patients suffered from severe beta thalassemia, and, after treatment, the number of blood transfusions they required fell by seventy-four per cent. Three of the nine no longer need any transfusions at all. The same is true of twelve of the thirteen patients with the less severe version of the disease. So far, the subjects of the trial have been observed for a maximum of forty-two months, but they will be monitored long into the future, to insure that the benefits of the therapy persist and cause no serious side effects. One early concern—that the procedure could disrupt the DNA of the stem cells, potentially triggering leukemia—has not, fortunately, come to fruition.

The results are stunning. What accounts for such dramatic success? Like all breakthroughs of its kind, this one relied on decades of incremental progress in parallel fields. The first attempts at bone-marrow transplantation date back to the mid-nineteen-fifties, when a Harvard-trained physician named E. Donnall Thomas began experimenting on dogs. These early tests, which stretched through the late sixties, almost invariably resulted in the patient’s death. In the ensuing years, though, the highly traumatic procedure evolved into a fine (though admittedly still traumatic) art. Gene therapy has come a long way, too. In the beta thalassemia trial, the successful introduction of the modified globin gene was made possible by a vector, or delivery system, that Philippe Leboulch, one of the co-authors of the paper, built on the back of a lentivirus, a naturally occurring pathogen that promiscuously infects cells. In an editorial accompanying the paper, Alessandra Biffi, of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, notes that gene therapies “targeting discrete groups of patients with certain immunodeficiencies and hemophilia” have recently shown promise.

The challenge now is finding ways to implement a complex, potentially life-saving treatment in parts of the world where medical care is limited. Established facilities for autologous marrow transplantation already exist in many developed nations, as do laboratories that can introduce a healthy globin gene into stem cells. But, in some parts of the world where beta thalassemia is most common, these facilities do not yet exist. There is not only a strong humanitarian argument in favor of funding and building them but also an economic one. Beta thalassemia is enormously expensive to treat in the long term, and gene therapy offers what amounts to a single-dose prescription. This devastating inherited disease that has been marked by debility and early death can be cured, if we have the will to make it a priority.