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Memorandum from Linus Pauling to Harvey Itano. January 20, 1950.
Pauling conveys his thoughts on the nature of sickle cell anemia. In so doing, he provide an interpretation of how sickled hemoglobin cells might behave at the molecular level, and also suggests a series of experiments that might shed further light on sickled hemoglobin cell dynamics.


Dr. Itano Linus Pauling Jan. 20, 1950

Nature of sickle cell hemoglobin

I think that sickle cell hemoglobin and normal human hemoglobin represent two ways of coiling the polypeptide chain characteristic of hemoglobin molecule, and that these two ways are rather stable, being the two stable configurations of the molecule. This is, of course, the globin molecule.

The evidence available so far indicates the difference in isoelectric point is not the result of a difference in amino acid composition of the globin. How, it has been reported, that when hemoglobin is denatured and renatured, it may occur in either one of two forms, differing in isoelectric point by 1.2 pH units. I think that these two forms correspond to normal human hemoglobin and sickle ceil anemia hemoglobin. Would you look up the article by Gralen and tell me what the isoelectric points are that he reported for the two forms.

I believe that we should repeat Gralen's work, and see if we can prove this point.

Moreover, I think that the two peaks which appear in your electrophoretic patterns of globin, both normal globin and sickle cell anemia globin, correspond to these two configurations. If we assume that the isoelectric point of globin is about the same as that of hemoglobin, 7 or a little less, and draw straight lines on a plot of mobility against pH to intersect the pH axis, the two lines passing through the observed mobilities for the slow components and the fast components in acetate buffer, at pH 4.64, we find that the intercepts differ by 0.23 pH units. The phosphate points do not give this result, the mobilities of the two components being reported

Dr. Itano -2- 1/20/50

as differing very little. I think that this may be due to a tendency of one of the globins to find phosphate preferentially, thus changing its charge. The place where the phosphate is bound is presumably the same place where I believe that heme is bound because I believe that you found that there was the same difference between sickle cell anemia hemoglobin and normal hemoglobin in phosphate buffer as in other buffer.

It seems to me that your experiments with globin, showing that the same globin comes from normal hemoglobin and sickle cell hemoglobin, is pretty good evidence for our point. I think that to repeat Gralen's experiment with the two hemoglobins would just about clinch the matter. Would you talk with me about making plans to have this work carried out?

It seems to me that one thing that we should consider is the possibility of converting one hemoglobin into the other simply by gentle heating, for a long time, at a temperature below the denaturation temperature. I suggest that we try the effect of heating both normal hemoglobin and sickle cell hemoglobin for several days, say, at a temperature of 58 °C, and then making electrophoretic patterns.

Linus Pauling:W

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