“At lunch Francis winged into the Eagle to tell everyone within hearing distance that we had found the secret of life”[1]
Cambridge has laid claim to many historic scientific achievements in the 800 years since the foundation of its University. Across this period, scientists with Cambridge associations have transformed our understanding of the natural world, from Newton’s laws of motion to Maxwell’s* theory of electromagnetism and much more besides. But one of Cambridge’s most revolutionary scientific contributions occurred not in the distant past, but comfortably within living memory.
2023 marks 70 years since the elucidation of the double helix structure of DNA. This discovery crystallised the physical essence of life into a single chemical structure, revolutionising our scientific understanding of biology and our cultural sense of what it means to be human. It also set the foundation for the modern discipline of biotechnology, upon which many DNA-centred innovations have been built. The DNA revolution has its past, present, and – we are confident – future rooted here in Cambridge.
"How can the events in space and time which take place within the spatial boundary of a living organism be accounted for by physics and chemistry?"[2]
Prior to the discovery of DNA’s double helix, some of our fundamental understandings of biology, which still endure today, had been established in Cambridge. In the mid-nineteenth century, Charles Darwin, who studied at Christ’s College, articulated the principles of evolution by natural selection in his book On the Origin of Species. This was a radical account of biological diversity and the common ancestry of life on Earth.
At around the same time as Darwin’s publication, Austrian monk Gregor Mendel was studying heredity in pea plants, meticulously quantifying how observable traits are passed from one generation to the next. Mendel explained his data using the idea of what we now call “genes”, inherited factors which determine the characteristics of future generations. Although their significance is now recognised, Mendel’s experiments were largely unnoticed until the dawn of the 20th century. That was when Cambridge geneticist William Bateson played a key role in popularising Mendel’s work, and coined the term “genetics” for the discipline which was to grow in Cambridge and beyond on the basis of Mendel’s laws.
Mendelian genetics and Darwinian natural selection sought to explain how heritable information is passed from parent to offspring, and how evolutionary change develops over time. However, although rich in theoretical insight, these ideas lacked mechanistic clarity. What was the chemical identity of Mendel’s gene, and what was the physical mechanism by which evolutionary change was communicated?
These questions were answered, in part, by experiments in the 1940s. This work pointed to deoxyribonucleic acid (DNA) as the hereditary molecule, the chemical constituent of genes and the carrier of genetic information. However, these findings were initially met with scepticism, with many insisting that DNA was too simple a molecule to be the genetic material. Work was still needed to identify how DNA could store and propagate genetic information. While the chemical composition of DNA was already known, the answers to these mechanistic questions would, as ever in chemistry, require the solution of DNA’s 3D chemical structure. This was a challenge to be seized by Cambridge’s Francis Crick and James Watson.
“We wish to suggest a structure for the salt of deoxyribose nucleic acid (D.N.A.). This structure has novel features which are of considerable biological interest”[3]
Originally a physicist, Briton Francis Crick made the transition to molecular biology after working on mines during the Second World War. American James Watson had spent time studying phage genetics before moving to Cambridge in 1951. Both found themselves working at the University of Cambridge’s esteemed Cavendish Laboratory, and “hit it off immediately”.[4] Both Crick and Watson were inspired by Erwin Schrödinger’s influential book What is Life?, which sparked a determination in the pair to elucidate the molecular basis of what Schrödinger called the “hereditary code script”. Together, they thus set out to solve the structure of DNA.
Crick and Watson embarked on an approach of “model-building”, experimenting with different 3D arrangements of model atoms made in the workshop, copper wire acting as a substitute for chemical bonds, twisting clamp stands to hold and reposition their structures in space. The aim was to arrive at a chemically acceptable model which fitted the published data on DNA. At times, they even used cardboard cut-outs of the key chemical groups to work out how the pieces fit together.
This model-building approach had previously been used successfully by American chemist Linus Pauling to solve other chemical structures. Pauling had now publicly declared his intention to solve the DNA structure. This was the man the Cambridge duo were racing to the crown.
James Watson’s personal account of this race is given in his book The Double Helix, an allegory of scientific competition, collaboration, credit, and controversy. We can now recognise that Crick and Watson were standing on the shoulders of others in the field who contributed the clues which the duo pieced together. Not least, the X-ray crystallographic data and insights of Cambridge alumna Rosalind Franklin, working in the King’s lab of Maurice Wilkins, were “absolutely critical”[5] to Crick and Watson’s model-building efforts. Franklin therefore remains highly conspicuous by her absence in the roll call of Cambridge Nobel laureates.
Nonetheless, it was Crick and Watson who were first across the finish line. On 28 February 1953, convinced that they had arrived at a model which must be the true structure of DNA, Francis Crick declared in the Eagle pub that the secret of life had been found. A short, but seminal, paper formally announcing their findings would follow later that year on 25 April.
“The structure was too pretty not to be true” 2
The structure published in 1953 is now instantly recognisable as the DNA double-helix. The exterior of the molecule comprises two separate sugar-phosphate strands running anti-parallel to one another and coiled helically around a common axis. Each strand comprises a sequence made from the ordering of different chemical groups known as “bases”, of which there are four, denoted by the letters A, T, C, and G. In the interior of the DNA molecule, hydrogen bonds form between bases on the neighbouring strands, holding the two together. T on one strand always pairs specifically with A on the other, and likewise C with G, such that each strand is complementary to the other.
In a master-stroke of understatement, Crick and Watson’s paper ends with the line: “it has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.” Owing to the specificity of the A-T / C-G base pairing, either strand of the helix could serve as a template for the synthesis of a new strand. As such, the double helix had revealed a means by which genetic material could be replicated and then propagated, mechanistically explaining a defining characteristic of the self-perpetuating chemical system we know as life.
In the years that followed, our understanding of this replication mechanism grew, as did our understanding of how genetic information is encoded in the helix by the specific sequence of A’s, T’s, C’s, and G’s. Following later work in Cambridge, Crick would articulate his “central dogma” of molecular biology, which set out how the genetic information encoded into DNA is used to direct the synthesis of proteins, which in turn determine biological traits.
The double helix had revealed the structural identity of Mendel’s genes. It also explained how heritable information, as well as mutations and variations in the genetic code, is copied and then passed from parent to offspring, accounting for heredity and the propagation of Darwinian evolutionary change. The mechanistic insights revealed by the double helix structure would pave the way for the modern discipline of biotechnology, with DNA at its centre.
“Then as now patents were given only for useful inventions, and at the time no one could conceive of a practical use for DNA”.5
The discovery of the double helix exposed the language of DNA. In the 70 years which followed, innovators and researchers would exploit this language to read, write, edit, and interpret the code-script of life.
Some of these innovations are now well-established. Examples include the routine use of DNA fingerprinting in forensic evidence and the use of recombinant DNA technology to induce microorganisms to produce useful gene products, one of the earliest examples being human insulin. In recent years, we have also become familiar with the use of PCR testing as a diagnostic technique and mRNA, a nucleic acid related to DNA, as a vaccination agent.
Other applications still have progress to make. The use of gene editing in agritech, with its potential to improve food security, is perhaps yet to reach its full potential, in part due to regulatory environments which are arguably lagging behind the rapid technological advances in the field, such as CRISPR genome editing. Meanwhile, gene therapy, which replaces genes in – or adds genes to – a patient genome to treat a genetic disorder, is still confronted by unresolved technical and societal challenges.
In the next article in our series, we turn our attention to sequencing technology. Sequencing aims to determine the specific sequence of A’s, T’s, C’s, and G’s in a sample of DNA. Early sequencing was pioneered in Cambridge by Frederick Sanger, and quickly developed to a scale which now enables the entire complement of human DNA – the human genome – to be sequenced in about a day. The medical insights provided by these techniques continue to grow. In our article, we will consider how the story of sequencing took Cambridge as its stage: from Sanger, to Solexa, and onto the multinational juggernaut of Illumina.
One of the first questions asked of James Watson in an early lecture on the double helix was “can you patent it?”5 While a scientific discovery cannot on its own qualify for a patent, patents can be used to protect and commercialise the myriad of inventions which rely on the insights gleaned from the double helix. From gene patents to genome editing technologies; from agritech to zymurgy; and from diagnostics to sequencing technologies, our attorneys at Marks & Clerk Cambridge have a great deal of experience in supporting innovators with all these technologies, and more. The current scale of our work in this area is quite remarkable, given that Marks & Clerk was founded only shortly after the work of Darwin and before DNA had even been identified as the hereditary molecule.
“Science and everyday life cannot and should not be separated”[6]
The first 70 years of the Cambridge DNA revolution saw the “exquisitely organised physics and chemistry”5 of life revealed in the double helix. The technologies sparked by the events of 1953 continue to multiply. We know from our experience that Cambridge remains a focus for these developments, with the city’s world-class life sciences innovators forming a key part of the UK technology sector, as we will explore in a later article.
We are still living through the early stages of the DNA revolution. Inextricably linked to the very nature of life itself, DNA technologies are almost uniquely placed to deliver solutions to problems of an inherently human nature, from medicine to food security. If you are one of the innovators working to continue the DNA story, whether you are in Cambridge or beyond, we hope to hear from you to explore how we can support your journey and shape DNA’s next 70 years.
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[1] James D. Watson: The Double Helix: A Personal Account of the Discovery of the Structure of DNA
[2] Erwin Schrödinger: What Is Life? The Physical Aspect of the Living Cell
[3] WATSON, J., CRICK, F. Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid. Nature 171, 737–738 (1953). https://doi.org/10.1038/171737a0
[4] Francis Crick: What Mad Pursuit: A personal View of Scientific Discovery
[5] James Watson: DNA: The Story of the Genetic Revolution
[6] Rosalind Franklin: letter to Ellis Franklin
* James Clerk Maxwell studied at the University of Cambridge. Following influential work on electromagnetism, thermodynamics, and more, Maxwell returned to Cambridge as the first Cavendish Professor, at the laboratory where Crick and Watson would later complete their work on DNA.
