Envisioning Viruses: Birkbeck College, London, 1953-1958
At Birkbeck College, Franklin was once more in a professional environment in which she felt respected and supported. Unlike King's, Birkbeck originated as a workingmen's college devoted to adult education, which gave it a much more egalitarian atmosphere. Moreover, the director of Biomolecular Research Laboratory was a scientist she had long admired, John Desmond Bernal. Bernal was a pioneer in x-ray crystallography and one of the first to recognize its application to biology. Along with Dorothy Hodgkin and others, he developed or refined many of the techniques and analytical methods that Franklin learned during her time in Paris. In 1934 he took the first ever x-ray diffraction pictures of a crystalline protein (pepsin), and in the late 1930s he and Isidore Fankuchen applied the technique to tobacco mosaic virus (TMV), producing a landmark study. Bernal had moved from Cambridge to Birkbeck in 1937, to chair the physics department, and established a lab devoted to problems in molecular biology in 1947. He was very glad to add Franklin to his research staff, and recommended that she take up the problem of TMV and other plant viruses.
Tobacco mosaic virus, which causes tobacco leaves to curl and discolor in patches (hence "mosaic") had been a model for virus studies since the 1880s; it was a simple, stable, and highly infectious organism. Understanding the structure of viruses was the first step in learning how they caused disease. By 1950 it was known that viruses consisted of protein and DNA or RNA (ribonucleic acid). Bernal and Fankuchen had found that TMV was composed of identical protein subunits. James Watson, during his hiatus from DNA modeling in 1952, worked briefly with TMV and established that the protein subunits were arranged in a spiral. Franklin's challenge was to find out whether the RNA was in the middle of the spiral, like a candle wick, or embedded in the proteins. She was aided in this work by Aaron Klug, then a postdoctoral fellow in theoretical physics and chemistry, and two research assistants, Kenneth Holmes and John Finch. For a time, the team also included Donald Caspar, an American biophysicist. When her Turner and Newall fellowship ended in 1954, Birkbeck arranged three years of support from the Agricultural Research Council (ARC) for Franklin's team.
Franklin encountered some strenuous opposition when she wrote up the results of her initial work on TMV in late 1954. She had found that TMV particles were of a uniform length, and that the protein subunits were of uniform size. She sent a draft of her article to Norman W. Pirie, an eminent plant virologist based at the Rothamsted Experimental Station. Pirie had supplied Franklin with the TMV for her research; he was also on the ARC, and had approved her research funding. Nevertheless, he objected to her conclusions, which he regarded as hasty. Her reply, though respectful, defended her results, which were correct. When she went ahead and published them, Pirie was so annoyed that he stopped supplying her with virus cultures, and she had to learn to grow her own. Probably due to Pirie's influence, she also encountered increasing resistance from the ARC when she sought to increase or extend funding for equipment and staff.
Fortunately, 1954 also marked Franklin's first visit to the United States. Invited to the Gordon Conference to give a paper on coal chemistry that summer, she also scraped together funding for visits to virus researchers at the Marine Biological Laboratory in Woods Hole (where her visit coincided with the 1954 hurricane), Washington University in St. Louis, the University of California in Berkeley, and California Institute of Technology in Pasadena, among others. She made new contacts and renewed older ones, building a network of colleagues whose work complemented and informed her own. She returned home with virus samples and promises of collaboration from leading American scientists such as Wendell Stanley and Barry Commoner.
By 1956, Franklin and her team were ready to put together a model of TMV. Donald Caspar, who came to work with Franklin in mid-1955, had discovered that TMV had a hole down the center of the proteins. Where, then, was the RNA? Franklin's x-ray diffraction data indicated that the RNA winds around the inside of the "doughnut hole" in a helical groove in the protein units. A new technique, called isomorphous replacement or heavy atom substitution (pioneered by Max Perutz and John Kendrew), made it possible to discern both the central hole and the groove. This technique adds atoms of mercury or lead to the virus protein at regular points on the structure. The differences between the diffraction patterns of this modified protein and the original are then used to calculate the phase angle of the diffracted wave in the original, which is needed to complete the three-dimensional picture. The team rapidly extended their studies to other plant viruses--turnip yellow mosaic (TYM), tomato bushy stunt, pea streak, and potato virus--often working with material contributed by colleagues worldwide.
When Franklin returned to the United States for the Gordon Conference and visits to virus research labs in the summer of 1956, she was at the top of her profession. She had assembled a fine research team, and their work produced a steady stream of publications. She had established a wide network of research contacts and collaborators, and was invited to meetings everywhere. (Wendell Stanley would later call her "an international courier of good will and scientific information.") And though she struggled with the ARC over funding (they disapproved of her working on "second hand material" from other labs, among other things) there was a good chance that a grant from the U.S. National Institutes of Health would provide alternative funding. While in America she was honored with a request from the Royal Institution for models of helical and spherical viruses, for an exhibit in the International Science Hall of the 1958 Brussels World Fair. (The five foot tall models--modified from early versions constructed from ping pong balls and plastic bicycle handlebar grips--were well received.)
During her trip, however, she began to experience sharp abdominal pains and swelling. When she returned to England in September her physician suspected ovarian cancer, and surgery confirmed it. She had a second surgery a month later, and returned to her lab in January 1957 feeling much better. During the following year, between surgeries and treatments, she had several long remissions and worked as much as possible. Work continued on plant viruses--the team prepared over a dozen papers for publication in 1956-57--and Franklin had also started planning a project examining polio virus. She applied for and received a three year research grant from the U.S. National Institutes of Health, ensuring the survival of her research group. In March 1958, the cancer advanced again, and Franklin returned to the hospital. She died on April 16, not quite 38 years old.
In the obituaries he wrote for the Times and Nature, J. D. Bernal praised her beautifully executed researches, carried out with apparently effortless skill, and her gift for organizing research projects. He noted, "As a scientist Miss Franklin was distinguished by extreme clarity and perfection in everything she undertook. Her photographs are among the most beautiful x-ray photographs of any substance ever taken." Her life, he concluded, was a perfect example of single-minded devotion to research.