23 October 1972
Dr. William G. Esmond
537 Stanford Road
Baltimore, Maryland 21229
Dear Dr. Esmond:
In answer to your letter, in which you mention your letter to me in 1954 in which you mention that you had found
that a partial transformation of ferrous sickle hemoglobin to ferric methemoglobin inhibited sickling in red cells, I must
say that I do not remember clearly enough to be sure about the matter. I suggest that you write to Harvey Itano, School of
Medicine, University of California, San Diego, La Jolla, California, to see what he remembers.
It is my memory, however, that I had through about this possibility much earlier, and had asked Dr. Itano to check
the sickling of erythrocytes containing ferrhemoglobin already in 1949. I had done work on ferrihemoglobin and its compounds
in the middle 1930;s, and one of the first questions that arose in my mind after the discovery of sickle-cell hemoglobin was
whether other hemoglobin derivatives that oxyhemoglobin and carbon monoxyhemoglobin would inhibit the sickling. I remember
that Dr. Itano told me that he had found that ferrihemoglobin inhibited the sickling, but I do not remember when it was that
he told me. In the paper by R.C.C. St. George and me in Science 114, 629 (1951) we presented the suggestion that erythrocytes
containing oxyhemoglobin or carbon monoxyhemoglobin do not sickle because of steric hindrance of the attached oxygen or carbon
monoxide molecule, and said that this steric-hindrance effect might be the distortion of the complementary sites through forcing
apart of layers of protein, as suggested by our isocyanide experiments. We then pointed out that the heme-heme interaction
energy in the oxidation of ferrohemoglobin to ferrihemoglobin is, we believed, a steric effect resulting from the ligation
of a water molecule to each iron atom in ferrihemoglobin. We also mentioned that human ferrihemoglobin forms orthorhombic
crystals isomorphous with those of oxyhemoglobin and carbon monoxyhemoglobin, whereas crystals of human ferrohemoglobin itself
are different. This work, published in 1951, indicated that ferrohemoglobin would show the same steric effects of oxyhemoglobin
and carbon monoxyhemoglobin, and accordingly would interfere with sickling in the same way.
Dr. William G. Esmond Page 2
23 Oct 1972
I am sure that I believed that ferrihemoglobin would prevent sickling in 1951, three years before your 1954 letter
was written. I do not know, however, when Dr. Itano verified the prediction in the laboratory.
I do not have my files at hand, but it will be possible for me to examine them in a few weeks, and I shall see what
I learn.
Sincerely,
cc: Dr. Harvey Itano
LP:bs
