GEL lab Blog (2) – guest feature

Why is Rosalind Franklin a hero in structural biology? by Dr Mark Williams

Nowadays, when mechanisms of viral infection and possible treatment are daily news, and typing “spike protein” into Google nets a million hits, it is perhaps hard to imagine that only 70 years ago essentially nothing was known about the structure and function of viruses.

Rosalind Franklin was one of the small group of scientists that profoundly altered our understanding of the mechanisms of life in the middle of last century. These pioneers imagined that life could be understood in terms of the structures of giant molecules (proteins, DNA and RNA). After years, and sometimes decades of work, they began to reveal the structures of those molecules in the 1950s, and discovered that what they had imagined was true. The extraordinary variety and beauty of the molecules, which continues to be revealed to this day, was unimaginable. Franklin’s personal history is intimately intertwined with the bigger historical picture of the structural biology revolution. Franklin herself made indelible contributions to our understanding of DNA and virus structure, but also the legacy of the research team she led at Birkbeck has been hugely influential.

The Imagineer-in-Chief of the structural biology revolution was Desmond Bernal, the founder of biomolecular research at Birkbeck. Before the Second World War, x-ray photographs [1] made by Bernal and his students and postdocs (then in Cambridge), had first shown that proteins and viruses had definite 3-dimensional structures with precisely arranged constituents down to the atomic level. A new idea was born – that life was the result of the combined actions of many different, precisely constructed nano-machines busily carrying out all the necessary chemical and physical processes.

After the War, Bernal began recruiting promising younger scientists to carry out research in structural biology at Birkbeck. Rosalind Franklin applied for a job in 1950, keen to work with a scientist she regarded as a “genius”, but did not get it. Instead, fatefully, she was offered an independent Fellowship by King’s College where the head of the department, John Randall, wanted her to do x-ray work on DNA reporting directly to him (failing to inform his deputy, Maurice Wilkins, who had been working on DNA up to that point, of the arrangement). Subsequent misunderstandings and antagonism between Franklin and Wilkins made the working environment at King’s unhappy for both of them, and led Wilkins to interact more with his old friend Francis Crick, and Crick’s new lab mate Jim Watson, in Cambridge than with Franklin.

Working with a PhD student, Ray Gosling, Franklin improved the experimental procedures and was able to show that long fibres of DNA had two different structures, which she called simply A and B, depending on how wet the fibres were. The A-form had been obtained previously by Wilkins and Gosling. The B-form was new and closer to the moisture content in living cells. The B-form photograph 51 (now a modern icon gracing our fifty-pence coins) seemed initially unpromising, having much less detail than the A-form. However, its simplicity was its strength, and by early 1953 Franklin had worked out that the B-form was helical with ten nucleotide layers per turn, with 2 or perhaps 3 chains and the phosphate groups on the outside. This and other geometric information about both forms made their way to Crick and Watson. They realised how the geometry could be combined with other chemical information to make an educated and inspired guess at the structure of DNA. Subsequently, in the summer of 1953, Franklin and Gosling showed that both the A and B photographs were consistent with Crick and Watson’s double helix model (the A-form being a bit squashed and twisted compared to the B).

The quality of the experimental analysis of DNA established Franklin as force to be reckoned with in this new field of structural biology. Rosalind had tried again to move to Birkbeck. This time, Bernal asked her to direct a new Virus Structure Group. Within two years the group had grown to five, including Aaron Klug, himself on an independent Fellowship, and who switched from working on proteins after meeting Franklin on the stairs of 21 Torrington Square and getting into discussions about unusual features in her diffraction photographs of Tobacco Mosaic Virus (TMV). Klug, a strong and imaginative theoretician, was able to find an explanation and “was basically hooked”. He later called that meeting “sheer luck” that “determined the rest of my life” [2]. He had found an important problem to work on and an inspirational colleague to work with. Klug would be Franklin’s closest collaborator over the next four years (and her chief advocate in the DNA controversy that erupted after the publication of Watson’s novelisation of history [3]).

During the final years of Franklin’s life, her team led the world in understanding virus structure. She designed better x-ray cameras and worked to improve the handling of the viral samples. She had developed fruitful collaborations with researchers in the US and Germany to source new viruses. The reward being much better photographs that were used to determine the first accurate information about the structure of any virus (TMV) and, thus, reveal the general principles by which all viruses are made [4]. Specifically, hundreds of identical protein subunits spontaneously assemble to make a large cage (called a capsid) that holds and protects the virus’ genetic material inside. All viruses of a given type were found to make capsids of identical size and shape – TMV’s is a long hollow rod made of helically stacked proteins with a single (not double) helical strand of RNA embedded within them. This rapid progress was helped by TMV also forming fibres, and thus a lot of the mathematical machinery that Franklin had learned in order to analyse DNA was immediately useful. However, they did not rest on familiar ground, the group expanded their reach to work on crystalline spherical human and plant viruses and began work on ribosomes.

In the year before her death, Franklin had obtained (with Klug as co-investigator) new funding to work on human viruses; the largest grant at Birkbeck up to that time. Structural models from her group, of TMV and poliovirus, were commissioned for the International Science Pavilion at the 1958 World’s Fair [5]; although she would not live to see the exhibition. In her too short life, she had a built a formidable reputation, and was widely admired.

However, a scientist is measured not only by their direct achievements but also their legacy. Franklin’s is pervasive. While the DNA story was largely moved forward by her former rivals at Cambridge, particularly Crick, who became a friend (she would holiday with the Cricks and stay with them while recovering from treatment during her illness), both of Franklin’s Birkbeck students, Ken Holmes and John Finch, would go on to become Fellows of the Royal Society; Klug would become its President. Holmes would continue to work on fibre diffraction and elucidate both the structure of TMV in atomic detail and the molecular mechanism of muscle contraction. Finch, working often with Klug, would determine detailed structures of poliovirus, papillomavirus and HIV, and work out the histone mechanism by which DNA is packed in the nucleus of cells. Klug and Don Caspar, a regular visitor to the Franklin lab [6], would develop a general theory of spherical virus architecture and thus understand why many plant and human viruses are structurally similar although not obviously related. Klug was awarded the 1982 Nobel Prize for Chemistry for his work in structural biology, particularly virus structure, and for developing the method of electron microscopy to solve large molecular structures. In his Nobel lecture he remarked “it was Rosalind Franklin who set me the example of tackling large and difficult problems. Had her life not been cut tragically short, she might well have stood in this place on an earlier occasion.”

Rosalind Franklin is a hero in structural biology, not only for technical achievement of taking photographs among “the most beautiful X-ray photographs of any substance ever” or the “extreme clarity and perfection of everything she undertook” or simply being a great leader “inspiring those who worked with her to reach the same high standards” [7] or for her essential contribution to the DNA story, but also for building the foundations for the detailed understanding of virus structure and function. A legacy that continues to be of great relevance in today’s viral pandemic.

Dr Mark Williams is a lecturer in biophysics at the Institute of Structural and Molecular Biology, Birkbeck.

[1] X-ray diffraction photographs are not simple pictures of a molecule, but instead only show features related to the distances between atoms of the molecule, and, to make things more difficult, do not usually show which distances belong to which atoms. Puzzling out the actual structure of large molecules from a diffraction photograph is a difficult task (albeit much more straight forward nowadays through developments in imaging detectors and computer hardware and software).

[2] Aaron Klug British Library recording

[3] Aaron Klug “Rosalind Franklin and the discovery of the structure of DNA” Nature 219, 808 (1968) and “Rosalind Franklin and the double helix” Nature 248,787 (1974).

[4] Aaron Klug manuscript “Professor Bernal and Virus research at Birkbeck College”. Wellcome Library Digital Archive – Rosalind Franklin Collection.

[5] John Finch’s photographs of Virus models and Franklin’s Lab

[6] Don Caspar interview for the CSHL Oral History project

[7] Bernal’s obituary of Rosalind Franklin in Nature.