A human recombinant haemoglobin designed for use as a blood substitute

THE need to develop a blood substitute is now urgent because of the increasing concern over blood-transmitted viral and bacterial pathogens1. Cell-free haemoglobin solutions2,3 and human haemoglobin synthesized in Escherichia coli4 and Saccharomyces cerevisiae5 have been investigated as potential oxygen-carrying substitutes for red blood cells. But these haemoglobins cannot be used as a blood substitute because (1) the oxygen affinity in the absence of 2,3-bisphosphoglycerate is too high to allow unloading of enough oxygen in the tissues6, and (2) they dissociate into αβ dimers7 that are cleared rapidly by renal filtration8–10, which can result in long-term kidney damage7–9. We have produced a human haemoglobin using an expression vector containing one gene encoding a mutant β-globin with decreased oxygen affinity and one duplicated, tandemly fused α-globin gene. Fusion of the two α-globin subunits increases the half-life of this haemoglobin molecule in vivo by preventing its dissociation into αβ dimers and therefore also eliminates renal toxicity.