Beyond the Double Helix

John writes ...

Introduction
 
It is now 72 years since the publication of the papers which presented the double helical structure of DNA to the scientific community (and eventually to the world). It is an event embedded both in the history and the folklore of molecular biology and genetics, as are the names of at least two of the scientists involved, namely Francis Crick and James Watson. Watson died on November 6th, aged 97. Later in this post I will present a brief obituary, However, before that I want to look back, ‘beyond the double helix’, well before 1953, to give us the historical context and to consider how science works in the ‘real world’.

Standing on the shoulders of giants
 
We need to go back to 1869 to note the actual discovery of DNA. A biologist called Friedrich Miescher, working in the chemistry laboratory of the University of Tübingen (which was actually in Tübingen Castle) used pus from clinical bandages as sources of human cells for chemical analysis. He discovered a compound rich in phosphate and nitrogenous bases which he showed to be located in the cell nucleus; he was also able to isolate the same compound from salmon sperm. He called the compound ‘nuclein’, which we now know to have been DNA, and later speculated that it might have some connection with inheritance. Miescher is one of the ‘forgotten people’ of DNA research and deserves to be much more widely known about than he actually is (see R. Dahm, 2005). 

Friedrich Miescher. Credit: Public Domain.

Three years before Miescher’s discovery, an Austrian friar, Gregor Mendel, Abbott of St Thomas’s Abbey, Brno (then in the Austro-Hungarian Empire, now in the Czech Republic), had published the findings from his experiments on inheritance of traits in pea plants. One of the key conclusions that he made from his work was that heritable traits were based in actual physical, albeit invisible, ‘factors’ which were passed on from generation to generation. However, the paper was not widely noticed until 1900, when it was rediscovered independently by Hugo de Vreis and Carl Correns; Mendel thus started to receive the credit that he deserved for his ground-breaking work. But what the Mendelian units of heredity (named ‘genes’ by Danish botanist, Wilhelm Johannsen in 1909) actually were, remained a mystery. 

Gregor Mendel. Credit: Public Domain.

A deoxyribonucleotide. A base, in this case adenine, is joined to deoxyribose phosphate.

Thus, by the early years of the 20th century, there were two paths across the genetic landscape. However, they were about to merge. Analysis of cell nuclei revealed the existence of a substance called ‘chromatin’ which contained nuclein/DNA and protein. Individual units of chromatin appear as chromosomes (‘coloured bodies’) prior to cell division and behave during division in a manner consistent with there being or containing the Mendelian units of heredity. By this time too, the general structure of DNA was being worked out, namely a large molecule made up of just four different deoxyribonucleotides. I need to unpack this: a nucleotide is nitrogenous base that is linked to a sugar-phosphate molecule. In DNA, the sugar is deoxy-ribose (ribose lacking an oxygen atom), hence, deoxyribonucleotides and deoxyribonucleic acid; in RNA, the sugar is ribose. How the four different deoxyribonucleotides were arranged along the length of the molecule was at that time unknown; one possible model was that DNA was a set of repeats of a tetra-deoxyribonucleotide, i.e., an array of linear groups of deoxyribonucleotides, each group containing one copy of each of the four types (A,C,G,T).

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So, chromosomes behave as if they contain genes, the Mendelian units of heredity. But which component of chromatin actually carries the genetic information? The general opinion was that proteins had the wide variety needed whereas it was thought that DNA, a molecule made up of only four building blocks, did not. At this point I need to introduce Frederick Griffith, a British medical scientist working at the Liverpool Royal Infirmary. In the late 1920s, he showed that a non-virulent form of Pneumococcus could be transformed into a virulent form if co-injected into mice with dead cells of a virulent strain. The dead cells thus contained something that provided the genetic information to confer virulence. Griffith called this the ‘transforming principle’ but he did not know what it was.

It took another 16 years after Griffith’s publication for the transforming principle to be identified. An American team, Oswald Avery, Colin MacLeod and Maclyn McCarty, working at the Rockefeller Institute for Medical Research, separated the cellular components of virulent-strain Pneumococcus, focussing in particular on proteins and DNA. These were then used in attempts to transform the non-virulent strain into the virulent strain. The results were clear – proteins did not transform the non-virulent strain but DNA did. DNA was thus shown to carry genetic information. It is my view that the experiments of Griffiths and of Avery, Macleod and McCarty were absolutely key moments in research on DNA which eventually led, via elucidation of the double helix, to modern molecular genetics.

The demonstration that DNA is the ‘genetic material’ inevitably led to a flurry of research directed at understanding its structure, both in terms of its detailed chemical composition and of its ‘architecture’. One of those who focussed on DNA was Erwin Chargaff, working at Columbia University in New York (having fled from Germany in 1935 because of Nazi attitudes to and policies about Jews). He analysed DNA from several different organisms and came up with two major findings, published in 1950, which became known as Chargaff’s rules. The first rule is that in any sample of DNA, the molecular concentration of the base A equals the molecular concentration of the base T and the molecular concentration of the base G equals the molecular concentration of the base C. Thus, somehow,  in synthesising DNA, the cell equates the amounts of the larger two-ring bases (A and G) specifically with the amounts of the smaller single-ring bases. How was that done? Chargaff’s second rule was that the overall concentration of A+T and G+C varies between organisms. This is to be expected if DNA is the genetic material (and also debunks the tetra-deoxyribonucleotide hypothesis that I mentioned earlier). Chargaff visited Cambridge in 1952 to talk about his work and while there he met Crick and Watson. He was not impressed. In an interview with a science historian, Horace Judson he said that ‘they impressed me by their extreme ignorance’, referring specifically to what he perceived as their ignorance of organic chemistry.

And so to the double helix
 
It has been quite a journey since 1869, traversing scientific landscapes in genetics and biochemistry/biophysics – but we are now in the very early 1950s. And here are Francis Crick and James Watson in Cambridge and Maurice Wilkins, Rosalind Franklin and Ray Gosling at King’s College, London. Gosling was a PhD student working under the direction of Franklin and later of Wilkins. It was he who took the famous ‘Photo 51’, an X-ray crystallographic image of DNA, showing clear evidence for a double helical structure. He and Franklin co-authored the second of the three papers published consecutively in the leading science research journal Nature on April 25th, 1953, the first, of course, being the major reveal of the double helix by Watson and Crick (see M.J.Tobin, 2004).The latter pair were fortunate to have had access to Photo 51 – or as Wikipedia puts it so tactfully: ‘The  crystallographic experiments of Franklin and Gosling, together with others by Wilkins, produced data that helped James Watson and Francis Crick to infer the structure of DNA.

Photo 51 – Image of DNA obtained by X-ray crystallography. Credit: Raymond Gosling/ King's College, London archive.

Ray Gosling in 2003, aged 76. Credit: Mary Gosling.

In a church service recently, I asked the congregation if they had heard of Watson and Crick (I emphasise that the question was entirely appropriate for the talk I was giving!). Almost everyone put their hand up. I then asked about Rosalind Franklin; about half of the congregation showed that they had heard of her. However, when I asked about Ray Gosling, only one person, a senior lecturer in Maths at Exeter University, raised his hand. Gosling, who died in 2015, aged 88, is one of those (nearly) forgotten heroes of science which is why I have focussed on him here. I need to add that after obtaining his PhD, he had a successful career in science, eventually becoming Professor of Physics Applied to Medicine at Guys Hospital Medical School.

Returning to DNA, the team at King’s College were already of the opinion that it had a helical structure and Crick, with his experience in and knowledge of biophysics, took it a bit further in proposing a double helix. But how did that tie in with the chemistry? He and Watson knew of Chargaff’s rules (see above) but had not yet developed the concept of base-pairing. Eventually however, after a lot of model building, some brilliant flashes of intuition and some pure guess-work, the double helical model ‘emerged’. The reason for Chargaff’s rule became clear: in the double helix, A or G in one strand are base-paired with, respectively T or C in the other. However, it was either a stroke of genius or a brilliant guess that, in order to fit the dimensions implied by the X-ray data, one strand had to be upside-down in relation to the other (the two strands are ‘anti-parallel’).

1953: James Watson (left) and Francis Crick (right) with their model of the double helix. Credit: University of Cambridge archive.

​When we look at the structure of DNA we can see how perfectly it is designed. The genetic code is a linear array of bases. There is no constraint on which base (deoxyribonucleotide) is joined to which base in that linear array, so enormous variety is possible. The only constraint is that a base in one strand determines which base occurs at that position in the opposite strand. The specificity of this base pairing means that DNA is copied accurately in preparation for cell division. The two strands separate and each acts a template for synthesis of its complement; the code is thus passed on. Further, specific base-pairing also means that working copies of a gene can be made in order for the cell to read and act on the code in that copy (the working copy is actually an RNA molecule, messenger RNA). As I have said elsewhere, the design of DNA is a work of genius.

One last question: would the London team have eventually come to the same conclusion? Most scientists who were aware of their work believe that they, and in particular, Franklin and Gosling, would have done so. But of course, the answer is irrelevant. Crick and Watson got there first.

A career in DNA
 
I think there can be little disagreement with the view that elucidation of the structure of DNA was the most significant discovery in biology in the 20th century. From it has flowed a vast amount of research and application of the findings of that research. The ‘golden age’ of research on genes was already underway when I arrived in Cambridge about a decade after the famous papers had been published and the place was obviously buzzing with excellence in nucleic acid and protein research. Crick was still there (Watson had gone back to the USA) and had moved from the Medical Research Council’s lab in the Cavendish Laboratory (Physics Department) to the same organisation’s newly established (but already very prestigious) Laboratory of Molecular Biology on the southern edge of the city.

I had gone to Cambridge with a strong interest in plants and vaguely expected to emerge from my Natural Sciences degree as a plant ecologist. However, I was thrilled by lectures on molecular genetics and biochemistry which pulled me to the lab rather than the field. In my PhD project, I looked at the onset of DNA replication as plant cells emerge from dormancy and that set me on a career in research on the biochemical mechanisms (and the control of those mechanisms) involved in gene expression and especially in DNA replication in plants. I am grateful for that career and feel, as Dame Dr Jane Goodall has also stated about her work on chimpanzees and on environmental conservation, that I was following God’s calling.

A much younger John analyses the results from a sequencing experiment in 1990. At that time we were still using the original, rather slow method, invented by Fred Sanger in 1977. Credit: University of Exeter.

Obituary – James Watson, 1928 -2025
 
It was obvious from an early age that James Watson was very bright. He went to the University of Chicago aged 15 and graduated with a degree in Zoology at 19. He was very interested in Ornithology but was persuaded by Schrödinger (yes, that Schrödinger) that he should study the more molecular and chemical aspects of biology. Thus, his PhD research, conducted at Indiana University, Bloomington, was on the properties of bacteriophages (viruses which infect bacteria). He then spent a year as a post-doctoral researcher in Copenhagen before joining Francis Crick in the Cavendish Laboratory in Cambridge. As is evident from what I have already written, their collaboration was very successful. They were very aware of the significance of their work – at the end of the day in which they had finally worked out the double helical structure, they walked into the Eagle pub in Bene't Street, Cambridge and announced: ‘We have discovered the secret of life’. In his book, The Double Helix, Watson says that he rarely saw Francis Crick in a modest mood – but those who knew them both, suggest that he could have said the same about himself.

On returning to the USA, Watson spent two years at the California Institute of Technology, working on the structure of RNA, followed by another year at the Cavendish Laboratory, before joining the academic faculty in the Biology Department at Harvard University at ‘the other Cambridge’ – across the river from Boston, Massachusetts. There, he was part of a group of scientists working on the roles of RNA in gene expression and who thus made a major contribution to our understanding of how genes actually work in the cell to direct protein synthesis. However, he was not always the easiest of colleagues. Those working in non-molecular aspects of Biology felt that he denigrated their work, believing it to be less important or less significant than his.

In 1968, Watson was appointed Director of the Cold Spring Harbor Laboratory on Long Island, New York. His time there was very successful. In the words of Tim Radford, former science correspondent of The Guardian, he turned the Laboratory into a ‘scientific powerhouse’ (see Tim Radford’s obituary here), especially in cancer genetics and molecular biology but also in several other fields, including plant molecular biology.

Following on from that success, in 1990 he was appointed as Director of the Human Genome Project. The project, initiated that year, was based at the National Institutes of Health in Bethesda, Maryland (although there were subsidiary centres such the Wellcome Sanger Institute, near Cambridge, UK). Having set up the main (US) branch of the project and ensured that genes sequences would be published (and not patented), Watson returned to Cold Spring Harbor in 1992, where he was appointed President of that institution. In respect of the Human Genome Project itself, as our readers will know already, it was a great success and by 2003 (50 years after the publication of the structure of DNA) a complete sequence of an ‘average’ human genome was published.
 
There can be no doubt that over the course of  a long career, James Watson has made a very large contribution to our knowledge of molecular biology. This was recognised and honoured by the world science community, and by universities and governments all over the globe.  However, in 2007, a shadow was cast over that career when he stated that people of African heritage were genetically less intelligent than people of Caucasian heritage. The Science Museum in London withdrew an invitation to lecture and he was asked to resign from his post at Cold Spring Harbor (although he was given an honorary fellowship). In 2019, in a TV documentary, he repeated those views and at that point the Cold Spring Harbor Laboratory withdrew his honorary emeritus fellowship. A sad end to an otherwise glittering career.
 
John Bryant
 
Topsham, Devon
November 2025