The 3-Hit model: Our work on the cell danger response (CDR)^1-11 led to the development of a 3-hit model of autism spectrum disorder [pdf]. In this model, ASD results from the sequential interaction of 3 factors: (1) DNA changes that sensitize mitochondrial metabolism, intracellular calcium handling, and ATP-related purinergic signaling to environmental change; (2) early prenatal or postnatal activation of the CDR by environmental factors like infection, immune dysregulation, metabolic disturbance, or toxicant exposure; and (3) prolonged or recurrent exposure to CDR-activating triggers for 3-6 months from the late 1 st trimester to 18-36 months of age. When mitochondrial, metabolic, and/or immune resources are usurped for too long during this critical window of neurodevelopment, the risk of ASD and several commonly co-occurring medical conditions is increased.

The 3-hit model integrates over 100 years of autism research. It doesn’t just change the way we think about ASD. It changes what we can do about it. Because the 2nd and 3rd hits are modifiable, the new model predicts that if CDR-activating air and water pollutants are decreased, new prenatal and newborn screening methods are used to identify the most vulnerable children, co-occurring medical conditions are treated, and new supports for metabolic and neuroimmune resilience are given to those children at increased risk, that like phenylketonuria (PKU)¹² , the most disabling symptoms of ASD can be prevented before they occur in some children, and decreased in others.

Once the symptoms of ASD have occurred, the model also predicts that new antipurinergic treatment trials of drugs like suramin can point the way to decreasing the most disabling symptoms in children and adults. Suramin is just the first in a new class of medicines that has not yet been developed. It is a steppingstone. It is not the final answer. If larger suramin trials are successful, many new medicines will be designed to calm the hypersensitive ATP signaling networks that cause the CDR to persist in ASD. These new medicines may one day help some children come off spectrum and reduce ASD’s most disabling symptoms in others.