Sickle Cell Anemia: Reexamining the First "Molecular Disease"

Introduction

One of the key studies marking the emergence of molecular paradigms in medicine is the 1949 article by Linus Pauling (1901–94), who showed that sickle cell anemia was due to an abnormal hemoglobin molecule. ¹ Although Vernon Ingram’s demonstration of the amino acid substitution in the beta-hemoglobin chain defined the molecular basis of sickle cell disease, ² Pauling’s study elucidated the nature of the disorder. His finding of a physicochemical abnormality in the hemoglobin molecules of sickle cell patients justifies the appellation “molecular disease.” ³

Pauling is celebrated in the historiography of sickle cell anemia research, which presents his work on the relationship between the chemical nature of hemoglobin and the structure of sickled cells as a turning point in the reorientation of research from clinical to molecular. ⁴ More broadly, because of his first demonstration of an abnormal protein by physicochemical methods, he is hailed as the key architect of molecular medicine, whose biomedical agenda was to dominate research for the rest of this century.

We suggest that the emphasis on the Pauling story reveals a romanticized and unsuccessful attempt to understand the difficult history of sickle cell anemia research. Furthermore, the story (as usually narrated) promotes the promise of a reductionist approach to medicine, serving to illustrate the power and eventual dominance offered by such a strategy. Our orientation reflects a somewhat different attitude; we contend that while the history of sickle cell anemia is indeed illustrative of the respective roles of clinician and chemist, a more subtle and complicated interplay of research traditions and methodologies was at work than simply the final successful application of chemistry to elucidating a complex disease. Setting Pauling’s accomplishment in context, we show how shifting research paradigms influenced successive redefinitions of sickle cell anemia along a broadly reductionist path. The years between 1910 and 1945 were a time of ambiguous characterizations of the basis of the disease. These initial attempts to define the pathophysiology of sickling as well as the genetics of the disorder reflect a complex array of ambiguous factors, not the least of which was the conceptual confusion concerning the nature of proteins during the 1920s, 1930s, and 1940s.

The complex nature of Pauling’s revolutionary efforts will be seen more clearly if the story of a chance encounter and a brilliant, novel insight is subjected to critical assessment. This popular narrative relates how William Castle and Pauling shared a train compartment returning from a meeting in Denver in 1945. ⁵ The two were serving on a committee eventually responsible for the publication of Vannevar Bush’s book Science, the Endless Frontier. According to Castle, while on the train from Denver to Chicago, he happened to mention to Pauling the phenomenon of birefringence of deoxygenated red blood cells, thinking that there might be interesting implications for molecular alignment. This comment, apparently placing the sickle cell problem in Pauling’s hands, and prompting him to unravel the explicit connection between molecular structure and clinical pathology, is taken as a critical moment in the history of the molecularization of medicine. The human and contingent element of this story is important because it proposes to bridge an apparent disjuncture in the history of sickle cell research by anecdotally representing a well-demarcated boundary between clinical and molecular paradigms.

For example, Maxwell Wintrobe emphasizes the function of chance in this incident and its implications for the history of medicine: “As it turned out, it was this incidental observation that, in the course of a chance conversation, was brought to the attention of Linus Pauling. For him the birefringence had some meaning. The resulting series of studies had a momentous impact on biomedical science.” ⁶ In The Eighth Day of Creation, Horace Judson characterizes Pauling’s contribution in this way: “The nature of the disease was first understood by Linus Pauling, with what was even for him an astounding flash of physical intuition.” ⁷ Narratives like this have glorified the entire episode, and more specifically, Pauling’s contribution. Pauling himself seems to have revised his own...