Monday, March 31, 2008

determining the structure of DNA

By the start of the 20th century, Cambridge stood out as one of the world's leading centers for science, of the same rank as the best German universities--­Heidelberg, Göttingen, Berlin, and Munich. Over the next 50 years, Cambridge would remain in that ­rarefied league, but Germany would be ­supplanted by the United States, much strengthened by its absorption of many of the better Jewish scientists forced to flee Hitler. England similarly benefited from the arrival of some extraordinary Jewish intellectuals. If Max Perutz had not had the good sense to leave ­Austria in 1936 as a young chemist, there would have been no reason for my now moving to the banks of the Cam.

Though winning the great struggle against Hitler had drained England financially, the country's intellectuals took pleasure in knowing that victory had been much of their own making. Without the physicists who provided radar for British aviators during the Battle of Britain, or the Enigma code breakers of Bletchley Park who successfully pinpointed the German U-boats assaulting the Allies' Atlantic convoys, things might have turned out very differently.

Emboldened by the war to think expansively, the then tiny Medical Research Council (MRC) Unit for the Study of Structure of Biological Systems was doing science in the early 1950s that most chemists and biologists thought ahead of its time. Using x-ray crystallography to establish the 3-D structure of proteins was likely to be orders of magnitude more difficult than solving the structures of small molecules like penicillin. Proteins were daunting objectives, not only because of size and irregularity but because the sequence of the amino acids along their polypeptide chains was still unknown. This obstacle, however, was likely soon to be overcome. The biochemist Fred Sanger, working less than half a mile away from Max Perutz and John Kendrew at the MRC lab, was far along the path to establishing the amino acid sequences of the two insulin polypeptides. Others following in his steps would soon be working out the amino acid sequences of many other proteins.

Polypeptide chains within proteins were then thought to have a mixture of regularly folded ­helical and ribboned sections intermixed with irregularly arranged blocks of amino acids. Less than a year before I arrived in England, the nature of the putative helical folds was still not settled, with the Cambridge trio of Perutz, Kendrew, and Sir Lawrence Bragg ­hoping to find their way by building Tinkertoy-like, 3-D ­models of helically folded polypeptide chains. Unfortunately, they got a local chemist's bad advice about the conformation of the peptide bond and, in late 1950, published a paper soon shown to be incorrect. Within months they were upstaged by Caltech's Linus ­Pauling, then widely regarded as the world's best chemist. Through structural studies on dipeptides, Pauling inferred that peptide bonds have strictly planar configurations, and in April 1951, he revealed to much fanfare the ­stereochemically pleasing alpha helix. Though Cambridge was momentarily stunned, Max Perutz quickly responded using a clever crystallographic insight to show that the chemically synthesized polypeptide ­polybenzylglutamate took up the alpha-helical conformation. Again the Cavendish group could view itself as a major player in protein crystallography.

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