Donald Caspar defined the rules that govern the self-assembly of simple viruses. This laid the groundwork for a new way of thinking about the molecular systems that regulate and drive all living cells. These rules have made it possible to characterize other viruses and then to design strategies to combat them. The same rules are also essential in the design of viral vectors to deliver gene therapy.
Viruses are usually made up of a strand of genetic material – DNA or RNA – enclosed in a layer of protein molecules. Using the laws of thermodynamics and the constraints of symmetry, Caspar cataloged the ways in which proteins can assemble to form the icosahedral shells of spherical viruses (notably rhinovirus and poliovirus) and the helical networks of virus-shaped viruses. stick (like Ebola).
By the mid-twentieth century, few protein structures had been resolved at atomic resolution. Caspar used limited data from x-ray crystallography, electron microscopy and fiber diffraction to identify characteristics of the prototype viruses. With an artistic eye, boundless curiosity and a passion for “connecting the dots”, he created exquisite sketches of viral structures and membranes, which still adorn the pages of many texts.
Caspar was born in 1927 in Ithaca, New York, when his father was a graduate student in chemistry at Cornell University. When he was ten, a family friend, crystallographer Isidor Fankuchen, told him about the recent discovery that rod-shaped tobacco mosaic virus (TMV) particles had a semi-crystalline structure, suggesting that the virus consisted of many identical units. . It took him on a lifelong journey to understand his structure and behavior. At the Brooklyn Polytechnic Institute in New York City, he was the youngest student in a two-week course in X-ray crystallography led by Fankuchen. After graduating from Cornell in physics, Caspar did his doctorate in TMV structure at Yale University in New Haven, Connecticut. He then held post-doctoral positions at the California Institute of Technology in Pasadena and the MRC Laboratory of Molecular Biology in Cambridge, UK.
At Cambridge in 1956, he set out to prove the theory put forward by James Watson and Francis Crick that spherical viral particles had cubic symmetry (in other words, that the protein envelope was made up of identical subunits arranged in a equivalent). He demonstrated that the tomato stunt virus had icosahedral symmetry. It soon became apparent that other viruses were also icosahedral. This, the most complex of cubic symmetries, requires 60 identical subunits. But biochemical data indicated that many viral particles had many more.
Caspar resolved this paradox in the late 1950s, working with Aaron Klug at Birkbeck College London, and drawing inspiration from the geodesic domes of architect Buckminster Fuller. He introduced near-equivalence – the idea that equivalent protein subunits could vary slightly in conformation to tightly seal viral shells. This opened up a universe of possibilities for the controlled assembly and disassembly of everything inside a living cell. Twenty years later, Caspar’s own lab has demonstrated that viral proteins can switch between non-equivalent conformations if necessary.
Caspar’s doctoral work on TMV served as the basis for an article published back to back with that of Rosalind Franklin in 1956 (DLD Caspar Nature 177, 928 (1956); RE Franklin Nature 177, 928-930; 1956). These located the viral RNA deep in the helical protein stems and marked the beginning of a friendship that lasted until Franklin’s death two years later. In 2008, their relationship was dramatized in Anna Ziegler’s play. Photograph 51, with romantic overtones that Don said were fictional.
In 1958, Caspar established what would become one of the most influential centers for the study of macromolecular structure: the Structural Biology Laboratory of the Children’s Cancer Research Foundation at Boston Children’s Hospital. The lab was transferred to Brandeis University in Waltham, Massachusetts, in 1972. In 1994, Caspar moved to the Institute of Molecular Biophysics at Florida State University in Tallahassee, where he spent the remainder of his career.
Writing was a struggle for Don. Editing a manuscript has often turned into an endless loop. He meant everything first – each statement was sort of a prerequisite for all the others. He was much better at talking. In fact, for those of us who collaborated with Don, it was never obvious that he was doing a job. He never stopped talking. He could eat all of his lunch without missing a beat. The group would set a lab timer before going to ask him a question. When the stopwatch struck, they could plead the need to verify an experiment.
Don’s many passions included gardening and Greek urns. On a walk through his garden in Cataumet, Cape Cod, Massachusetts, he told about the family, genus, and common name of each plant and tree, and explained why he chose a particular variety and color for each location. Go with him to a museum, and it was never time to leave without visiting the ballot boxes. He was married for 50 years to Gwladys Caspar, one of the first biosafety officers at Harvard University in Cambridge, Massachusetts. His quick guide to Biosafety Levels 1-4 (Don’t Eat It, Touch It, Breathe It, and Do It Here) is still being taught.
Don was brilliant, kind, and always enthusiastic about new ideas – his own and those of others. Her support for young scientists was extraordinary, as was her advocacy for women in science. Don’s deep insight and broad perspective will be sorely missed.