In 1953 a significant change occurred in Pauling's scientific life, he developed an interest in mental disorders and began applying his concept of molecular disease to mental deficiencies and mental illnesses. Pauling usually demonstrated the link by discussing sickle cell anemia and phenylketonuria (also know as PKU and phenylpyruvic oligophrenia). Phenylketonuria is a hereditary disease in which babies develop physical and mental disabilities after birth because their bodies can not break down phenylpyruvic acid. Articles about the treatment of phenylketonuria started appearing in the early 1950s, and by 1961 many realized the link between diet and disposition of those suffering from phenylketonuria. When Pauling gained an interest in phenylketonuria in the mid-1950s it was known that phenylketonuria manifests itself in persons who are homozygous recessive for this genetic abnormality. Likewise, sickle cell anemia affects those who are homozygous recessive for sickle cell hemoglobin.

Starting in the fall of 1955, Pauling began discussing phenylketonuria in his speeches about molecular disease and drew parallels between phenylketonuria and sickle cell anemia. For example, Pauling mentioned that phenylketonuria is caused by an inborn error resulting in the sufferer's inability to manufacture the enzyme that converts phenylalanine to tyrosine. Ultimately, Pauling foresaw a day when artificial enzymes would be used to treat these types of diseases. In addition, Pauling stated that most mental disorders were molecular diseases that resulted from abnormal concentrations of molecules within the body and he thought that sickle cell anemia could be used as a template for understanding mental ailments. "The discovery of the abnormal hemoglobins has provided us with a far deeper understanding of the hereditary hemolytic anemias than existed before. In the same way, much may be done in increasing our understanding of phenylpyruvic oligophrenia [PKU]."

By the mid-1950s, Pauling had associated himself with mental ailments and had unequivocally connected mental disorders to his concept of molecular disease.