Viruses From Structure to Biology

Picornavirus Structure

Solving the structure of the icosahedral plant viruses was a major achievement, but it wasn't clear that it had a profound impact on virologists at the time. In the early 1980s virologists were more involved in determining the strategy of viral replication; they were identifying oncogenes in retroviruses. Perhaps the plant virologists were more attuned to how structure could provide new ways for them to think about problems such as that of virus assembly. Solving the structure of the plant viruses, however, did mean that the structure of other viruses, animal viruses, might also be determined. Picornaviruses seemed the obvious next goal. One reason was that polio virus had been crystallized by Schaffer and Schwerdt in 1955 (Proc. Natl. Acad. Sci. 41:1020-1023). Steve Harrison tells the following story (is it apocryphal?):

Apparently Schaffer had crystallized the Mahoney strain of polio virus and his wife was going to bring it to England in her pocketbook. The custom agent asked her what it was and when she said it was poliovirus, he said: "Lady, you can't bring poliovirus into England". She responded: "But it is crystalline". The custom agent must have realized the importance of this as he let her pass.

Fred Schaffer commented on this quote and wrote:
I dug out my 1957 correspondence with Rosalind Franklin and 1957-1959 correspondence with Aaron Klug to refresh my memory. In an earlier visit by Rosalind to the UC Berkeley Virus Lab we discussed feasibility of X-ray crystallography of poliovirus; at that time the remaining material from the earlier crystallization was not suitable. When much better crystals of Mahoney strain (Biochim. Biophys. Acta 28:241-246, 1958) became available we initiated plans for the work. Indeed, the above story is in part apocryphal. It was many years later that the Schaffers made their first trip to England. Carlton Schwerdt, who had moved on to Stanford University, offered to hand-carry the first samples to England, accompanied by a "to whom it may concern" letter explaining the nature and destination of the material. Rosalind had suggested not attempting to clear the way with British Customs bureaucracy in advance, but to label the package "nucleoprotein". Anyway the sealed package including ice for temperature control was too large for a pocketbook, but a large handbag may have been appropriate. I do not recall if Carlton Schwerdt's wife Patsy accompanied him on that trip to meetings in Europe, but if so, she could have been carrying the package through customs. Preliminary work was done with those crystals, but problems arose with handling them, so a few months later a second shipment was sent commercially via Pan Am. Rosalind Franklin then became too ill to continue work, and it was this latter shipment that provided material for the Finch and Klug paper.

And John Finch wrote that:
Aaron Klug confirms that it was indeed Patsy Schwerdt who brought the polio crystals through customs with the "crystals."

Steve continued:
These or similar crystals had been given to Rosalind Franklin for X-ray diffraction analysis in 1957. After Dr. Franklin's untimely death the following year, John Finch and Aaron Klug continued the work and dedicated their paper to her memory (Nature 183:1709-1714,1959). Their precession photographs indicated that polio virus had icosahedral symmetry: the authors point out that the structure conformed to the ideas of Crick and Watson about spherical viruses. They wrote" "It is probably safe to conclude that there are no structural grounds for distinguishing the smaller animal viruses from the plant viruses". But would they have been surprised at how similar the detailed structures of these different viruses were?

Jim Hogle came to Steve's lab to learn crystallography planning to solve the structure of polio virus. Jim had been a graduate student at the University of Wisconsin where he came under the influence of Roland Rueckert. Roland seems to have been responsible for connecting Jim with Steve Harrison for the eventual goal of solving the structure of polio virus and also for influencing Michael Rossmann to tackle rhinoviruses Rossmann Oral History

The structure of rhinovirus 14 (HRV14) - the common cold virus - was reported by Michael and his collaborators in 1985 (Nature 317:145-153). For the X-ray crystallographers there were several highlights: The data had been collected at the Cornell High energy Synchrotron (CHESS) providing one of the early examples of the power of this source of high energy radiation. The initial 6 angstrom map could be extended to 3.5 angstroms by multiple cycles of molecular replacement. The value of molecular replacement - first proposed by Michael in 1960 - was now established. Rossmann Oral History

There were significant results for the virologists too. Barbara Sherry and Roland Rueckert from the University of Wisconsin had isolated a panel of monoclonal antibodies that neutralized HRV14. They had selected virus mutants resistant to neutralization and identified four major immunogenic neutralization sites. According to Michael  Rossmann Oral History

"We had just traced the chain and we then looked for these escape mutations and we knew that they should be in groups. Barbara had found that many of these escape mutants were on quite unrelated peptides and even (different) subunits. But when we traced them and found them on the map, we recognized that not only were the mutations - the escape mutations - on the surface of the virus where they should be if that region is interacting with neutralizing antibodies, but they were also grouped together. She had shown that the monoclonal antibodies could be divided into 4 groups and now we could see that the corresponding escape mutations were also grouped in the same way. It was so exciting! We saw that the pattern was starting to emerge and we started placing on the map the next escape mutations of Barbara's. There must have been something like 10 of these mutations. And we wondered - is it going to maintain this pattern? I found it difficult. I had to walk away. I was so worried and excited. Would the escape mutations go where we expected them to be? Then I would come back and the others had traced them. Thank goodness it came out. We hadn't got the tracing very well established and we had to find out exactly where we were. So this was maybe the most exciting day I ever had - tracing those escape mutations."

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| Introduction | Some historical highlights: structural virology and virology |
| Solving the Structure of Icosahedral Plant Viruses | Picornavirus Structure | Poliovirus | Polio
The Influenza Virus Hemagglutinin
| The Influenza Virus Neuraminidase |
Issues of Science and Society |contributors|
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