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
