Abstract
A quarter of a century ago, sickle cell disease (SCD) was mainly viewed as a typical genetic disease inherited as a classical Mendelian trait. Therefore, the main focus concerning SCD was on diagnosis, meaning, genotyping, and identification of homozygous and heterozygous individuals carrying the relevant HbS mutant allele. Nowadays, it is well established that sickle cell disease is indeed the result of homozygosis for the HbS variant, although this single feature is not capable of explaining the highly diverse clinical presentation of SCD. In fact, an important feature of SCD is the chronic inflammation that accompanies the sickling of erythrocytes. In this manuscript, we will revisit the early evidence of inflammation in SCD and review what was uncovered during the last 25 years. Here, we describe Sickle cell anemia as a major participant in the history of science. In fact, SCD was the first genetic disease where the causal mutation was identified and is also the first disease for which treatment through genome editing was approved, making this disease a landmark in the road of molecular biology.