Molecular Medicine: University of Texas, Dallas
Unlocking genetic on/off switches to fool the body into healing itself.
Growing up in Wisconsin, Betty Pace lost a good friend to sickle-cell anemia. Right then, in junior high, she decided to spend her life trying to find a cure. Now a physician and researcher, Pace, 49, may be closing in.
Sickle-cell anemia is caused by an error
in the gene that produces hemoglobin, the oxygen-carrying component of red blood cells. The defective hemoglobin molecules
form long, sticky polymers, making the blood cells sickle-shaped instead of round. These
abnormal cells clog up blood passageways; ultimately, vital organs are starved for oxygen. Diseases arising from a single faulty gene
are prime candidates for a treatment known as gene therapy: Just replace the faulty gene with the correct version, the thinking goes, and—voil!—a cure. The standard approach is to place the desired DNA in the shell of a neutralized virus and set it loose in the patient. But it's tricky to get the desirable gene to insert itself correctly in the patient's genetic machinery. In 30 years, gene therapy has partially cured only a few patients, and in 2002 two of the method's poster children contracted leukemia as a result of their treatments. In January, the FDA suspended gene therapy trials in humans—making the field a troubled setting for a dedicated investigator like Pace.
But Pace's approach sidesteps traditional gene therapy. Her work doesn't involve shoehorning new DNA into cells but rather coaxing the body to heal itself. To counter sickle-cell anemia, she aims to
provoke the body to activate the fetal hemoglobin gene. This gene, which makes a protein that helps growing fetuses siphon the oxygen they need from their mother's bloodstream, goes dormant at birth. What makes it of interest to Pace is that it never carries the sickling mutation, and if enough fetal hemoglobin is present in adult blood, sticky polymers will not form, even in the presence of mutated proteins made by the adult sickle-cell gene.
Pace searches for transcription factors—proteins that attach to the fetal hemoglobin gene and turn it on. This year she logged a major victory: She found one that, in cell culture at least, provides a promising boost in fetal hemoglobin production. Next, Pace will test it
in mice. Human trials are years off, but if she succeeds, doctors will
ultimately be able to remove stem cells from an afflicted person's bone marrow, activate the gene, then return the cells to the patient, where they would produce the curative protein forever.
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