In 1968, after a quest lasting 30 years, X-ray analysis of crystalline horse hemoglobin at last reached the stage when I could build a model of its atomic structure. The amino acid sequences of human globin are largely homologous to those of horse globin, which made me confident that their structures are the same. By then, the amino acid substitutions responsible for many abnormal human hemoglobins had been determined. The world authority on them was the late Hermann Lehmann, Professor of Clinical Biochemistry at the University of Cambridge, who worked in the hospital just across the road from our Laboratory of Molecular Biology. I asked him to come over to see if there was any correlation between the symptoms caused by the different amino acids substituted in the abnormal hemoglobin and their positions in the atomic model. The day we spent going through them proved one of the most exciting in our scientific lives. We found hemoglobin to be insensitive to replacements of most amino acid residues on its surface, with the notable exception of sickle cell hemoglobin. On the other hand, we found the molecule to be extremely sensitive to even quite small alterations of internal non-polar contacts, especially those near the hemes. Replacements at the contact between the a and P subunits affected respiratory function.
In sickle cell hemoglobin an external glutamate was replaced by a valine. We wrote: A non-polar instead at a polar residue at a surface position would suffice to make each molecule adhere to a complementary site at a neighbouring one, that site being created by the conformational change from oxy to deoxy haemoglobin'. This was soon proved to be correct. We published our findings under the title: 'The Molecular Pathology of Human Haemoglobin'. Our paper marked a turning point because it was the first time that the symptoms of diseases could be interpreted in terms of changes in the atomic structure of the affected protein. In the years that followed, the structure of the contact between the valine of one molecule of sickle cell hemoglobin and that of the complementary site of its neighbor became known in some detail. At a meeting at Arden House near Washington in 1980, several colleagues and I decided to use this knowledge for the design of anti-sickling drugs, but after an effort lasting 10 years, we realized that we were running up against a brick wall. Luckily, the work was not entirely wasted, because we found a series of compounds that lower the oxygen affinity of hemoglobin and we realized that this might be clinically useful. One of those compounds, designed by DJ Abraham at the University of Virginia in Richmond, is now entering phase 3 clinical trials. On the other hand, our failure to find a drug against sickle cell anemia, even when its cause was known in atomic detail, made me realize the extreme difficulty of finding drugs to correct a malfunction of a protein that is caused by a single amino acid substitution. Most thalassemias are due not to amino acid substitutions, but to either complete or partial failure to synthesize a- or P-globin chains. Weath-erall's chapter shows that, at the genetic level, there may be literally hundreds of different genetic lesions responsible for that failure. Correction of such lesions is now the subject of intensive work in many laboratories.
Early in the next century, the human genome will be complete. It will reveal the amino acid sequences of all the 100000 or so different proteins of which we are made. Many of these proteins are still unknown. To discover their functions, the next project now under discussion is a billion dollar effort to determine the structures of all the thousands of unknown proteins within 10 years. By then we shall know the identity of the proteins responsible for most of the several thousand different genetic diseases. Will this lead to effective treatment or will medical geneticists be in the same position as doctors were early in this century when the famous physician Sir William Osler confined their task to the establishment of diagnoses? Shall we know the cause of every genetic disease without a cure?
Our only hope lies in somatic gene therapy. AK Stewart's chapter on Molecular Therapeutics describes the many ingenious methods now under development. So far, none of these has produced lasting effects, apparently because the transferred genes are not integrated into the mammalian genome, but a large literature already grown up bears testimony to the great efforts now underway to overcome this problem.
My much-loved teacher William Lawrence Bragg used to say 'If you go on hammering away at a problem, eventually it seems to get tired, lies down and lets you catch itLet us hope that somatic gene therapy will soon get tired.
Perutz MF, Lehmann H. (1968) Molecular pathology of human haemoglobin. Nature, 219, 902-909.
Perutz MF, Muirhead H, Cox JM, Goaman LCG. (1968) Three-dimensional Fourier synthesis of horse oxyhaemoglobin at 2.8Ä resolution: the atomic model. Nature, 219, 131-139.
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