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Don C. Wiley (1944-2001)

The accidental death of Don C. Wiley, Harvard U., on November 16, 2001, has deeply saddened the scientific community worldwide. Don went to Tufts U. as an under graduate, and was a graduate student in biophysics at Harvard U. with William Lipscomb. Don became an assistant professor in the department of biochemistry and molecular biophysics at Harvard and spent a sabbatical at the medical research council (MRC) Cambridge and the National Inst. for Medical Research, Mill Hill London, in 1976 pursuing crystallization and diffraction studies of the Hong Kong 1968 influenza virus hemagglutinin with Joan Skehel. I became Don’s first postdoctoral fellow in 1977. Those years were to be as exciting as one could ever imagine in a scientific venture. We received monthly shipments of the HA protein from Skehel shipped in hand-blown glass viles lovingly cradled in fluffy white cotton wool. Countless oscillation photographs of both native and heavy atom derivatives of HA were collected on an Elliott X-ray GX-6 machine. Only one suitable heavy atom derivative was found, which necessitated averaging and solvent flattening concepts that had only been used in cases of extensive non-crystallographic symmetry. Don adapted the Bricogne Program that Steve Harrison had used for tomato bushy stunt virus (TBSV), provoking a great deal of skepticism even from Bricogne who questioned whether three-fold averaging of data phased on a single derivative with no anomalous information could work. It did! Cycle by cycle, the map improved culminating with a 75% phase difference from beginning to end – one could now visualize the outline of the long trimer of the HA stacked like Lincoln logs head to tail around a four-fold screw axis. The structure was one of the first to be built on the computer, rather than in a Richard’s box, using the BILDER program of Bob Diamond, as modified by Bob Ladner at Harvard. The structure was amazing with its globular head and long helical coiled-coil system. Don mapped the antigenic variations of the influenza virus from 1968 to 1977 onto the HA structure. The results were astounding as the mutations mapped into four discrete areas on the HA structure – it appeared that for a new viral epidemic strain to emerge, mutations were required in four regions on the surface. It was immediately apparent that carbohydrate could mask the surface and help render the virus invisible to the immune system, whereas the few highly exposed regions accommodated most of the amino acid variation and acted as a decoy to avert the immune response away from the conserved receptor binding site. The impact of these structure on the virology and immunology communities was profound. The HA was to become the model for how the enveloped viruses fuse their membranes with the host cell. Don followed up that work with the structures of fusion domains of HIV-1 gp41 and Ebola virus. In 1987, the major histocompatibility (MHC) complex class molecule, HLA-A2 was unmasked by Don, Pamela Bjorkman, and Jack Strominger and another historic milestone was achieved. The HLA structure revealed a completely new fold, now known as the MHC fold. Between the α-helices and the β-sheet floor was a long, narrow groove in which extra density was seen that could not be accounted for by atoms of the MHC. The density was a mixture of bound short peptides that are derived from digestion of intact protein antigens by the proteasome. The polymorphic residues of the class I MHC mapped beautifully onto the walls and floor of the groove exactly where the peptide contacted the MHC. At last, one could visualize how the MHC was able to present peptides to the T cell receptor. It would take another five years to untangle the details of the peptide interaction due to the difficulty of making single peptide MHC complexes. It is hard to capture the vastness of the contributions that Don made to virology, immunology, structural biology, molecular biology, cell biology, and biochemistry. His legacy is monumental. It epitomizes how structural work can facilitate a deep understanding of complex biological processes. Don was awarded the Gairdner Foundation Award (1994), the Lasker Award (1995) and Japan Prize (1999). he became a Howard Hughes Medical Ins. investigator in 1987 and was elected to the national academy of sciences in 1991. Don was a captivating speaker whose reasoning was painstaking and thorough. He was the consummate scientist that most aspire to be. In our sorrow over this terrible tragedy, we celebrate and pay tribute to the tremendous career that brought so many insights into really important scientific problems.

Ian A. Wilson, Nature Structural Biology, Mar. 2002, Vol. 9, No. 33
8 July 2009