In this letter Heidelberger expressed specific reservations about several experimental results Linus Pauling, the world's
preeminent physical chemist at the time, had presented as evidence for his hypothesis regarding the formation and chemical
structure of antibodies and the location of the sites at which they bind to antigens.
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1942-10-23 (October 23, 1942)
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Antigens and Antibodies: Heidelberger and The Rise of Quantitative Immunochemistry, 1928-1954
I have just had my first opportunity of really studying your "antibody" paper in the August J. Exp. Med. and am writing
you because of some rather disquieting reservations that seem indicated.
Let us take, for example, the "most promising" alkali-denaturation experiment with methyl blue: Would a control,
without dye, slow appreciable loss of nitrogen as ammonia? Is anything known about the sensitivity of j-globulin under these
All in all, this experiment shows only that a sample of globulin, in longer contact with dye and alkali, binds more dye than
one in shorter contact. In view of our ideas on the mechanism of specific precipitation and antigen-excess solubility, which
are only special cases of precipitation and solution in general, hapten effects are to be expected whether or not antibody
has been produced. Again, I think, Dean's experiments with Isamine Blue and normal sera, showing a complete parallel
with immune precipitation, are very pertinent as an analogy.
I was also greatly disturbed to find that the arsenic-azo material fails to precipitate south of ph 6.5. While it is quite
remarkable that your product shows as great similarity to antibody as it does, true antibodies react with homologous antigen
independently of pH between roughly 5 and 9 - a really enormous range of H ion concentration. Is it not, therefore, stretching
a point to call your altered globulin "antibody"? Again there is a very disturbing analogy: the precipitation of
non- antibody (Pn type-specific) globulin in antipneumococcus horse sera (J, Immunol., 1941, 42, 1) by nucleic acid, which
is both pH - and salt-sensitive. Again, I do not think solubility in excess happen in the arsenic dye experiments necessarily
indicates the involvement antibody.
The pneumococcus III experiments do not seem to decide any of these questions, either.
I do hope you will not mind these reservations, because you know I would like to see a real, airtight configuration of what
I consider a brilliant deduction, and that you will want to furnish such evidence in your next publication.