The unexpected pathway to the creation of the HbA1c test and the discovery of AGE’s

This story begins at a social affair in New York for a group of haematologists. At that time I was an Assistant Professor at the Rockefeller University trying without success to isolate erythropoietin from theurine of patients with aplastic anaemia. One of the participants, Alan Schecter, mentioned that there had been a recent report of the successful treatment for sickle cell anaemia crisis in patients with large amounts of urea [2]. The rationale that was given by the investigators was that urea would disrupt the polymerizedhaemoglobinS in the redcells that cause entrapment in capillaries and in turn cause severe pain and tissue damage. I responded that I could not question the validity of the clinical trials, but I could not believe that one could ever give enough urea to achieve this because the amounts of urea needed to break hydrogen bonds are in the molar range. However, the possibility existed that the clinical effects could be the result of the carbamylation of HbS with cyanate because urea in solution is in equilibrium with ammonium and cyanate ions. The finding that urea solutions were in equilibriumwith cyanate that couldreactwithproteinshadbeenfirstobservedwith the enzyme ribonuclease [3]. Working with James Manning and Martha Fedorko, we were able to demonstrate that cyanate could react with the amino terminal valines of haemoglobin S and prevent the sickling of cells following deoxygenation in vitro [4] and invivo [5].