Developmental Disorders, Arrest & Reversal

Lately we have been hearing a lot about reversal experiments in mice. One might wonder, “if they can reverse Rett syndrome or Fragile X syndrome, or hopefully MECP2 duplication syndrome in mice, why the heck don’t they reverse it in my kid?” Sometimes it seems like mice must have better healthcare than people.

It is important to understand both the significance and limits of this kind of research. In order to do that we need to think about two theories about how these syndromes develop.  In one theory, the genetic differences result in differences in how the individual’s cells and organs develop.  As a simple example, we can imagine having an extra copy of a gene that would make the individual grow taller. If our imaginary child was 15 years old,  7 feet tall, and still growing rapidly and we found a way to silence the extra growth gene, we might expect his growth to slow down, or even stop completely, but we couldn’t expect the growth that had already occurred to reverse itself and make his height decrease. So we might hope to arrest his growth but we probably can’t reverse it. This kind of situation applies to many neurodevelopmental disorders. For example, in PKU disease, individuals can’t metabolize the amino acid phenylalanine. It results in a toxic backup that causes intellectual disabilities and other problems. If we exclude phenylalanine from the child’s diet, the condition stops getting worse, but the damage already done does not go away. It can be arrested but it is not reversible.

Many other conditions, however, are reversible. For example, with most infectious diseases, once the infection is gone, the symptoms get better rapidly.

The reversal experiments are designed to determine whether the symptoms of Rett syndrome, MECP2 duplication, or other conditions are reversible. The results with Rett syndrome and Fragile-X are encouraging. They suggest that if we find a way to address the underlying under or overactivity of the genes, a lot of the symptoms might improve or even be eliminated.

HOWEVER, they do not tell us how to control or compensate for the genetic under or overactivity. The Rett syndrome lab animals used in these studies are specifically engineered not only to have the syndrome but also to have a kind of biochemical switch that allows the critical genes it to be turned on and off. This cannot be done with our family members who have the syndrome.The Fragile-X research actually points to a chemical or drug that produces reversal, and this is goes a step further.

So, these experiments ARE an important step because they tell us that it searching for a way to normalize this gene activity or compensate for it, is likely to have real benefits for people affected  by these syndromes. But they are only one step and there is a long road ahead.

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