Linus Pauling molecularly characterized the first Mendelian Disease: Sickle Cell Anemia

Sickle cell anemia affects 4.4m people, and 43m are carriers of the trait.

It is characterized by the crescent, or sickle shape, of the red blood cells of those affected by the disease.

James Herrick first discovered sickle-shaped blood cells in a patient suffering from severe anemia in 1910.

Through subsequent observation it was realized that there was an asymptomatic form of the disease, sickle cell trait.

In those individuals it appeared that they had a mixture of normal and sickle blood cells.

Further study within the families of these individuals in 1923 revealed that sickle cell was hereditary or passed down from parents to their offspring.

And because those with sickle cell trait appeared to have a 50/50 mix of sickle/normal blood cells, it was determined that this was a recessive Mendelian disease.

Linus Pauling, a titan of early molecular biology, was no stranger to blood or the protein hemoglobin and spent many years in the 1930’s studying hemoglobin’s interactions with oxygen.

Pauling had a suspicion that the structure of proteins played a vital role in their function and was first introduced to sickle cell anemia in 1945.

He hypothesized that the sickling of cells could be related to a change in the structure of hemoglobin since red blood cells are literally just bags that contain a boat load of hemoglobin protein.

So he and his team, Harvey Itano and John Singer, tried to figure out a way that they could show that a difference in the structure of hemoglobin was the cause of sickle cell anemia.

After a bit of trial and error, they stumbled on the use of electrophoresis, a brand-new technique at the time, that allowed for the separation of molecules based on their electrical charge.

The results of their experiments can be seen in the figure above.

They separated and quantified 4 sets of blood samples using Longsworth scanning diagrams. A) shows normal hemoglobin, B) is hemoglobin from a sickle cell patient, C) is hemoglobin from a patient with sickle cell trait, and D) is a mixture of A and B. The arrow denotes a point of reference for comparing the diagrams.

This work demonstrates that there is a molecular basis for sickle cell anemia and that changes to a gene can alter the structure of a protein.

In the case of sickle cell, this functional relationship extends further because in the 1950’s, the trait was shown to be protective of malaria.

This explains evolutionarily why this disease is found in individuals of African descent; however, it fueled an unfounded fear of 'black blood' throughout the early 1900's.