Pauling first heard of sickle cell anemia in 1945 from Dr. William B. Castle of Harvard Medical School and Boston City Hospital. In the mid-1940s, Pauling and Castle were on a Medical Advisory Committee together that compiled a report for Vannevar Bush's influential Science: The Endless Frontier, which outlined post-war funding for medical research. All of the Palmer Committee members, excluding Pauling, were physicians. During 1945 Castle talked about sickle cell anemia to some committee members and mentioned that the red blood cells of sickle cell anemia patients change from a normal shape in the arterial blood to a crescent shape in the venous blood.

Upon hearing this, Pauling immediately jumped to some conclusions that were based on the various scientific works that he had conducted in the previous decade. In particular he drew from his intimate knowledge of immunology and of hemoglobin and its derivatives: oxyhemoglobin and carbonmonoxyhemoglobin. Two important ideas dawned on Pauling that he and his colleagues followed up on. First, based upon the information that only deoxygenated blood sickles, he concluded that hemoglobin was involved. Secondly, he suggested that the structure of sickle cell hemoglobin might differ from that of normal hemoglobin and that the structural difference caused deoxygenated sickle cell hemoglobin to bond to itself and convert the red blood cells into a crescent shape.

Pauling immediately wanted to follow-up on his intuition and asked Castle if he could try some experiments, to which Castle agreed. Pauling also spoke with another member of the committee, Dr. Ed Doisy of St. Louis University Medical School, who suggested that Pauling admit his recently graduated medical student, Harvey A. Itano, to the Ph.D. program in chemistry at Caltech. Itano arrived at Caltech in September 1946 to work on this project.