The discovery of an interaction among the four hemes made it obvious that they must be touching, but in science what is obvious is not necessarily true. When the structure of hemoglobin was finally solved, the hemes were found to lie in isolated pockets on the surface of the subunits. Without contact between them how could one of them sense whether the others had combined with oxygen? And how could as heterogeneous a collection of chemical agents as protons, chloride ions, carbon dioxide, and diphosphoglycerate influence the oxygen equilibrium curve in a similar way? It did not seem plausible that any of them could bind directly to the hemes or that all of them could bind at any other common site, although there again it turned out we were wrong. To add to the mystery, none of these agents affected the oxygen equilibrium of myoglobin or of isolated subunits of hemoglobin. We now know that all the cooperative effects disappear if the hemoglobin molecule is merely split in half, but this vital clue was missed. Like Agatha Christie, Nature kept it to the last to make the story more exciting. There are two ways out of an impasse in science: to experiment or to think. By temperament, perhaps, I experimented, whereas Jacques Monod thought.
~ Max F. Perutz
