Organizations Involved:

American Society for Microbiology (PI William Summers)
American Society for Virology (PI Sondra Schlesinger)
Society for Neurosciences (PI was Gordon Shepherd, but will now be Larry Kruger at UCLA)

The first virology web site will be: The biology of viruses as learned from structural studies

One of the stated goals of developing Internet technologies to contribute to the scientific historical record is to obtain broad participation in the creation of that record. This Web site devoted to structure and biological activity of viruses would attempt to explore the history of how knowledge of the structure of viruses at atomic resolution has impinged on the more biological studies of viruses. We would expect to obtain contributions from two overlapping groups of scientists; those who were responsible for determining the structures and those whose work was directly influenced by that information.

In the last few years there has been an explosive increase in the number of structures of virus proteins and of intact viruses that have been determined by x-ray diffraction; for the latter there are increasing contributions of structure determination from cryoelectron microscopy. We expect (and hope) that some of the contributions to this Web site will come from scientists directly involved in structure determination. At the same time we want to establish a balance between the history of the essential technological advances that made some of the structure work possible and an historical discussion of the impact of that structural knowledge on the development of biological concepts as well as on the design of antiviral drugs.

Two examples given below represent milestones in the development of our understanding of virus structure. The scientists responsible for the determination of these structures are leaders in the field and can contribute a valuable historical perspective on this subject. Information about these structures has had broad implications in the field of molecular virology and in the development of vaccines. The historical documentation of these contributions would be much richer if the impact of the structural information on virological research were obtained from a more diverse group of scientists. These two examples serve as potential subjects for this Web site.

(i) influenza hemagglutinin (HA) - The structure of the influenza HA was determined by I.A. Wilson, J.J. Skehel and D.C. Wiley (Nature 289:366-373, 1981) and was the first viral glycoprotein for which a high resolution structure was obtained. The HA is essential for several functions that the virus must carry out during its life cycle. These include binding to the cell surface, fusion with the cellular endocytic membrane leading to the release of the viral ribonucleoprotein into the cytoplasm of the cell and finally assembly and budding of the influenza virus particle from the infected cell. Antibodies directed against HA should protect against disease but the ability of this protein to undergo antigenic drift has thwarted attempts to produce effective long-lasting vaccines. The regions of the molecule that interact with antibodies to neutralize the virus have been located on the three-dimensional structure as have the amino acids that change to allow the virus to survive the previously protective immune response. An important, but still not well-understood function of the HA is its ability to undergo a conformational change at low pH which mediates fusion between the viral and endocytic membrane of the cell. Very recent structural studies are beginning to shed light on the mechanism of this fusion event. Studies with HA have also provided a model for receptor-virus interactions, for localization of proteins to the cell surface and for understanding the role of modifications such as N-linked glycosylation in the stability and function of membrane proteins.

(ii) Icosahedral RNA viruses - The plant viruses, tomato bushy stunt virus (TBSV) and southern bean mosaic virus (SBMV)were the first viruses for which high resolution structures were obtained. The structure of TBSV was determined by Stephen Harrison (Nature 276:368-373,1978); that of SBMV by Michael Rossmann and his collaborators(Nature 286:33-39,1980). The influence of earlier work, particularly the concept of quasi equivalence described by Caspar and Klug could also be an important subject for this historical record.

Structural studies of these plant viruses were instrumental in developing ideas of assembly and disassembly of icosahedral viruses. They paved the way for the determination of the structures of animal viruses such as the rhinoviruses (Rossmann et al Nature 317:145-153,1985) and poliovirus(Hogle et al. Science 229:1358-1365,1985). Knowledge of the latter structures has had extensive impact on a number of areas of interest including virus antibody interactions, virus - receptor recognition and mechanisms of antiviral activity. These subjects are important to a wide spectrum of scientists who could contribute to the historical record on the Web.

The first Microbiology Web site will be: Plasmids.
Plasmids are small (usually) extrachromomal circular DNA molecules which have two essential functions in bacterial cells: they must replicate them selves and they much partition the replicated copies to the daughter cells during cell division. In addition, however, plasmids may carry genes for many different sorts of functions. Some plasmids carry genes which facilitate their transfer from one cell to another. This sort of plasmid, when it also encodes genes conferring resistance to antibiotics, can result in muliple drug resistance rapidly spreading to many related organisms (the so-called "resistance transfer factor"). Other plasmids may recombine with the host cell chromosome and become integrated and mimic cellular genes. Some versions of these kinds of plasmids confer upon the whole chromosome the ability to be transferred to another cell, a rather primative sexual process discovered by Lederberg and Tatum in 1946, known as bacterial mating.

The ability to isolate and manipulate plasmids outside the cell, add DNA segements to the plasmid and then re-introduce it into the cell in a functional form, has given rise to the procedures and processes of recombinant DNA technology. The plasmid is the "vector" for engineered genes to be put into cells and maintained there by the normal replication of the plasmid itself. Thus, plasmids have been central to the "revolution" in molecular biology brought on by the ability to synthesize and manipulate DNA sequences in the test tube.

The field of plasmid biology is about 40 years old, e.g., the small book "Episomes" by Allan M. Campbell, published in 1968, was one of the first comprehensive treatments of the subject. Many of the key early participants are active but in, or near retirement. There is one journal specifically devoted to the field (Plasmid, Elsivier) and specialty meetings are held. Thus, both identification of the members of this field and mechanisms for recruitment will start with these sources.

[Information on Neurosciences not available at this point. ]

For questions please contact:

Sondra Schlesinger
Box 8230
Dept. of Molecular Microbiology
Washington University School of Medicine
660 South Euclid Ave
St. Louis, MO 63110-1093

Ph. 314-362-2746
FAX 314-362-1232
Email: sondra@borcim.wustl.edu