Genetic mutations are usually the source of debilitating disease. But, for a number of rare inherited blood and skin disorders, spontaneous DNA changes can repair and even reverse disease symptoms. Mike May explores the therapeutic potential of this ‘natural gene therapy’.
As a child, John bruised easily. After playing in the neighborhood park, he would come home with bruises on his arms and legs from injuries he never even noticed. And, as the youngest of six siblings growing up in the northeastern US, injury-inducing horseplay would seem inevitable around the house, too. But his parents had a strict rule: “Unbeknownst to me, none of my siblings were permitted to touch me,” John says.
John (not his real name) suffers from a rare disease called Wiskott-Aldrich syndrome (WAS), an X-linked recessive disorder characterized by recurrent infections, low platelet counts and an increased risk of autoimmune disorders and cancer. Yet, unlike two of his older brothers, both of whom died from the disease when they were each just five years old, John has managed to cope with his illness well into his 40s thanks to a phenomenon known as ‘revertant mosaicism’, in which genetic mutations spontaneously correct themselves.
At some point in John’s past, the defective WAS gene — which codes for a protein found in blood stem cells involved in regulating the actin cytoskeleton — randomly mutated back to a working form in a subset of his blood cells. These corrected cells then proliferated through natural selection, producing a mixture of functional and flawed cells. Although John, a former space flight instructor and now a stay-at-home dad in central Texas, has battled his share of medical problems — including non-Hodgkin’s lymphoma, which is currently in remission — his functional blood cells maintain enough working tissue that John describes his health as “generally good.”
In discussing conditions like John’s, Jouni Uitto, director of Thomas Jefferson University’s Institute of Molecular Medicine in Philadelphia, says, “This is nature’s attempt at gene therapy. It’s proof of principle that you can fix those mutations.”
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