Don C. Wiley
1944 - 2001

Don Wiley changed how we picture molecular organization at the cell surface. Indeed, he helped to create how we picture it. His two monumental contributions, the structures of influenza virus hemagglutinin in its various states and the structures of class I and class II MHC molecules in combination with peptides, superantigens, and T cell receptors, redefined molecular virology and immunology. He was one of the pioneers who transformed the specialty then known as protein crystallography into the discipline we now call structural biology.

Don burst upon the scene of protein crystallography in 1971, at the landmark Cold Spring Harbor Symposium on Protein Structure. Fresh from the triumph of a 5.5 Å structure of aspartate transcarbamoylase (ATCase) and a recently completed PhD thesis, he arrived from Cambridge in a newly acquired sports car. He continued to cut a dashing figure throughout the meeting. He had been recruited (from Tufts) to the Biophysics graduate program at Harvard by Donald Caspar, who remained an important intellectual influence, but he was ultimately lured by the ATCase project to pursue thesis research in William Lipscomb's laboratory in the Department of Chemistry. In 1967, the structural basis of allosteric regulation was a major (and contentious) problem. It represented the next level of structural complexity, beyond the three or four simple enzymes for which atomic resolution models were then at hand. By 1971, Don had changed all that, not yet by fully solving the problem of course that took another two decades of work in Lipscomb's laboratory but by defining the route to an answer.

I first met Don shortly after he arrived at Harvard. I was a student in Caspar's laboratory in the so-called Jimmy Fund Building of the Children's Cancer Research Foundation, and Don did an extended rotation there. He carried out diffraction experiments on lipid phases, perhaps nucleating his career-long interest in membranes. We collaborated while he was a graduate student, working out how to use the newly introduced rotating-drum film scanners to index and integrate precession and, later, oscillation photographs. We were recruited by the Department of Biochemistry and Molecular Biology in the same year, and when Don accepted his appointment, a few months after I accepted mine, he came to propose that we set up our laboratories together. Sitting in my tutor's room in Lowell House, we fantasized how would we build up what we called structural molecular biology (a phrase we had learned from Caspar and Carolyn Cohen) amidst the informational molecular biology then reigning in Cambridge, Massachusetts.

Don joined the Harvard faculty immediately upon completing his degree an unusual step that circumvented the conventional postdoctoral route. The lack of a transitional period, within which to find a worthy research goal, was the source of considerable stress, as Don recounted in an interview with Sondra Schlesinger (see http://virologyhistory.wustl.edu/wiley.htm). For Don was not a person to consider, even for a moment, a bread-and butter project to back up his more ambitious strivings. His determination never to waste time on something ordinary was probably reinforced by the influence of Jim Watson, an intense scientific presence in the Harvard of the 60s and 70s. In any case, by 1974, he had found a direction that would dominate the rest of his career, by seizing upon viral surface glycoproteins the influenza virus hemagglutinin (HA) in particular as a route toward unraveling the molecular mechanisms of cell-cell recognition. Of Don's success in turning this part of cell biology into crystallography, Max Perutz once wrote that Don had now done the impossible twice. The first time was, of course, his graduate-student success with ATCase.

Skeptics tried to dissuade Don from studying viral glycoproteins. These were known to have somewhat variable glycosylation, and there were even doubts about the rigidity of their protein components. Don figured that he would worry about such issues when the time came: you can always talk yourself out of a challenge, and the real trick is to avoid crippling inhibitions.

Don was enormously fortunate in finding John Skehel as a collaborator on the HA project, as was John in finding Don. Skehel published an account of the preparation and apparent crystallization of soluble HA in 1972. Don contacted him when he first read the paper, almost two years later. They built up a striking scientific and personal friendship. Don spent six months in Skehel's laboratory in Mill Hill, pushing the project forward, and they spoke on the telephone at least weekly, and sometimes more often, during the ensuing decades. Don and I were also jointly fortunate that Harvard had allowed us to establish a shared laboratory. Each of us was able to contribute to the other's progress and to provide encouragement in the inevitable intervals of perceived despair. By 1977, Don had also succeeded in recruiting a superb postdoctoral fellow, Ian Wilson (now at the Scripps Research Institute), who was instrumental in pushing the HA effort to completion.

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