Why doesn’t gene replacement cure our diseases?

I am often asked about why knowing the complete human genome isn’t enough to treat mankind’s diseases. Knowing what gene is missing and replacing that gene through gene therapy seems a logical approach to curing diseases, but biology may not respond to logical approaches; One reason may be due to the “contextual-reprogramming” of the mammalian genome. The human genome has close to 20,000 genes. To advance therapeutics the field has sought to recognize what many of these genes do. Through reverse genetics, companies and academic labs will delete specific genes, generate animal models with the deleted genes, and recognize the behavioral outcomes of those deletions; knowledge of which can spur potential genetic or protein targets to treat human disorders. While this has proven success in a few cases, therapies that replace the disease genes often prove to not cure the diseases. The major complication with such a logical approach is the immense reprogramming of some of the 19,999 genes when in the context of the deleted gene of interest (context genes). Consider a funnel that you fill with 15 rocks (genes): each one has its specific position and function that is specific to that position. If you were to remove one rock positioned somewhere in the middle of that funnel you’ve done more than just remove one rock and its function; you’ve now altered the position of a few of the remaining 14 rocks in the funnel (and yes gravity is necessary for this analogy). This “displacement” response in genes makes therapeutic approaches challenging as alterations in many of the 19,999 genes may be the causes of the disease, and their altered functions irreversible when the target gene is therapeutically replaced. The challenge in the field is how to de-displace these displaced genes or their protein products so that therapies more directly treat the diseases. Image


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