Sunday, 16 June 2019

Talk : Nottingham's role in discovering the structure of DNA

Interesting British Science Association talk recently by Prof Stephen Harding at the University of Nottingham on Nottingham's role in the discovery of the structure of DNA. A video of the talk, with a great deal more information than is in these partial notes, can be found on Youtube.

Prof Harding
Where DNA is located in cells(source)

Prof Harding began by taking the audience back to Germany in 1869, where Johanns Friedrich Miescher first discovered and isolated nucleic acid from white blood cells.

Later, in 1910, Phoebus Levene, who was working at the Rockefeller Institute in New York, identified the components of DNA but believed that they were organised in a fixed, repeating structure, and thus unable to carry information. Instead, the scientific consensus at the time was that the proteins in chromosones were where the genetic information was encoded. DNA was viewed as perhaps being a store of phosphorus.

Moving forward to 1938, Prof Harding talked about Florence Bell and William Astbury at Leeds University who performed some of the first X-ray crystallography[a method of determining chemical structure] studies of DNA (see here for more information). Although they had impure samples they were able to discern a layered structure and the distance between the DNA units - information that would be valuable to later researchers.

It was then noted that the DNA content of cells doubled just before cell division, putting the focus back on DNA as a possible location for the genetic code. This view was bolstered by experiments by Oswald Avery, again at the Rockefeller Institute.

It was around this time that Nottingham (or rather University College Nottingham, as it was then) played an important role in the understanding of DNA, with three key papers being published in 1947 by Professor John Masson Gulland and colleagues Denis Jordan, Cedric Threlfall, and Michael Creeth, with the work being done in what is now B34.9, in the languages section of the Trent Building, Nottingham University Campus.

The first paper described how to produce high quality DNA samples, critical to obtaining useful information from crystallography studies. The paper showed how an untracentrifuge could be used to improve the purity of the samples, together with rigouous attention to detail throughout the testing process:
Gulland JM, Jordan D. O., and Threlfall C. J., (1947) Deoxypentose nucleic acids. Part I. Preparation of the tetrasodium salt of the deoxypentose nucleic acid of calf thymus. J Chem Soc. 1947; 25: 1129–31

The second paper investigated the viscosity of DNA and found the viscosity to be relatively high, suggesting that it was a long rod like molecule, unlike protein molecules which were typical round and compact.
Creeth, J.M., Gulland, J.M. and Jordan, D.O. (1947) Deoxypentose nucleic acids. Part III. Viscosity and streaming birefringence of solutions of the sodium salt of the deoxypentose nucleic acid of calf thymus. J. Chem. Soc. 1947,25 1141–1145

The third paper showed that something was preventing the amine groups from reacting, suggesting the presence of hydrogen bonds. In his PhD thesis of 1947, Creeth correctly predicted that DNA consisted of two chains, connected by hydrogen bonds that were strong enough to hold the chains together but weak enough to allow the two chains to be pulled apart and copied during cell division. Creeth also suggested that DNA might have a helical form, based on the tendency of nature to coil up large natural structures.
JM Gulland; DO Jordan; HF Taylor; (1947) Deoxypentose nucleic acids; Part II electrometric titration of the acidic and the basic groups of the deoxypentose nucleic acid of calf thymus. J Chem Soc. 1947; 25:1131–41.

Comparison of Creeth's proposed DNA structure (left) with actual DNA structure(right)(link)
Model of Creeth's DNA structure
Soon after, however, the team dispersed which ended the departments frontline research into DNA.

These papers proved very useful to later researchers. Watson James Watson (who, together with Francis Crick finally decoded the structure of DNA) wrote that "...a rereading of J. M. Gulland's and D. O. Jordan's papers...made me finally realize the strength of their conclusion that a large fraction, if not all, of the bases formed hydrogen bonds to other bases."

Creeth also later commented “In hindsight, we had been given not just a glimpse, but a good view of that particular bonding that is nothing less than the key to life on this planet.”

In 1950 to so-called "Chargraff Rules" were formed, one of which stated that, of the four "letters" in the DNA code - C, A G and T; there is an equal amount of A and T and equal amounts of C and G. This is important as it hints at the way DNA stores information. If you have one strand of the double helix, you can work out what the other strand will be as A will always be paired with T and C will always be paired with G. This is also how nature can take DNA and make an exact copy.

1952 X ray diffraction images of highly purified DNA. The value of this can be seen when comparing the X-ray images of DNA from Florence Bell in 1938 (left) and Rosalind Franklin (right) - the cross seen at the centre of the image on the right was a clear indicator of a twisted helix structure.

1938 Xray Diffraction (Bell and Astbury)

1952 X ray, with central cross showing evidence of a helical structure (Franklin and Gosling)(source)

Finally, and famously, it was Watson and Crick who, in 1953, were able to determine the structure of DNA, using information from a number of sources. Prof Harding mentioned that the story is well told in the 1987 Jeff Goldblum starring film "Race for the Double Helix"/"Life Story" which is available here.

Worth noting that there were a great many researchers also trying to solve this puzzle. For example, just a few months earlier, in Feb 1953, , Months earlier, Linus Pauling and Robert Corey, in the US, proposed a model for nucleic acids containing three intertwined chains, with the phosphates near the axis, and the bases on the outside. Pauling later said that his lack of access to the high quality Xray crystallography images being generated in the UK at the time by Rosalind Franklin were a factor in his structure being incorrect.

Detailed structure of DNA, showing location of hydrogen bonds and Sugar-Phosphate backbones

Below are a number of links to further articles on Nottingham's role in the story of DNA:

If you want to really dig deep, Wiki page on Molecular Biology is a fascinating place to start.