On the 25th April 1953, Francis Crick and James Watson at the University of Cambridge published their suggestion for the structure of DNA in Nature, a discovery made possible by X-ray diffraction studies from Rosalind Franklin and Maurice Wilkins at King's College London, whose papers were also published in the same edition.
Their work formed the basis for modern biomedical research and scientists have built on this knowledge, improving our understanding of who we are, how genes are passed down, and how these processes vary person to person.
We spoke to Crick scientists about the latest developments in our understanding of all things DNA.
Three papers published in Nature on 25 April 1953 described the structure of DNA, using X-ray diffraction images (top left).
How the discovery of the double helix changed research
“The structure of DNA provided a beautiful explanation for two of the great ideas of the 19th century – Mendel’s conception of the gene and Darwin’s discovery of evolution by natural selection. During the 20th century, it became clear that DNA was the molecule responsible for heredity, laying the ground for Watson, Crick, Franklin and Wilkins’s model.
“The structure of DNA is incredibly elegant: two long strands wrap around each other in a double helix, zipped up by highly specific base pairs. The structure explains how DNA can be copied – after pulling the two strands apart, each strand can act as a template, using the specific base pairing to make another double helix.
“The exquisite accuracy of this process ensures efficient transmission of genetic information to the next generation. But occasional errors in this process – known as mutations – can subtly change the cell’s ‘blueprint’. These mutations have been responsible for generating the diversity of life on earth, but are also responsible for turning normal cells into cancer cells.”
DNA replication – how to copy six billion base pairs
John’s team at the Crick studies the processes involved in copying DNA.
“What we usually see in a textbook diagram of DNA is short segment of around 20 base pairs. In reality our genomes are huge, each cell containing more than six billion base pairs of DNA. These have to be copied every time a cell divides, and our bodies contain a lot of cells – amazingly, the DNA our bodies make in just one minute is enough to stretch from the earth to the moon!
“From more than forty years of cancer research, we know that mutations in lots of different genes can cause cancer. But most people don’t get cancer – showing that DNA replication is normally an accurate and robust process.
“Nonetheless problems can occur, and when they do, this increases the likelihood of cancer. To copy our genomes quickly and efficiently, DNA replication begins from thousands of ‘origins’, or locations, distributed across our genomes. Over the past three decades we have used a variety of approaches to build a detailed picture of how replication begins at these origins and how the process is controlled to make sure each origin is used just once in every cell cycle.
“We’re only just beginning to grapple with how all the many processes that occur on the same DNA template like DNA replication, DNA repair and gene transcription are coordinated. What happens when the machines involved in these different processes collide? How does DNA replication deal with DNA damage which is occurring all the time? And how is the normally exquisite regulation of DNA replication disrupted in cancer?”
Epigenetics – how our environment impacts our genes
“The term epigenetics was coined even before the discovery of the structure of DNA – but our understanding of how epigenetics influences health and disease lags behind genetics.
“Genetics is the study of how traits are passed from one generation to the next through DNA, whereas epigenetics involves changes on top of DNA which influence traits. These changes alter how the DNA is read, which is why cells have the same instructions but different functions. If DNA is the book, epigenetics are marks made over time on the pages which help to interpret what the words mean.
“Cancer was one of the first diseases to be linked to epigenetic changes, and we are now learning how important they are in cancer cells that evade treatment. Besides cancer, a lot of epigenetic research has helped our understanding of ageing. We’re also now starting to see that some epigenetic changes can even be passed down generations, impacting the heritability of common diseases
“New technologies are being produced which can tell us information about the genetic and epigenetic changes at the same time and hopefully give us more understanding about diseases. What will also be important is understanding how epigenetic modifications all interact with each other.”
Sequencing– figuring out the message encoded in DNA
“After the discovery of the structure of DNA, the next piece of the puzzle was to figure out the message encoded in its strands. Fred Sanger was responsible for one of the first methods for sequencing DNA, which involves finding the exact order of the four nucleotides A, C, T and G.
“But Sanger sequencing only allowed us to read a few hundred nucleotides at a time. We’ve seen a huge improvement in technology since then which has brought down time and cost. We now have Illumina machines, which can sequence 50 human genomes in about two days for about £200 per genome – a huge difference from the Human Genome Project, which took more than 13 years to sequence just one human genome and costed billions.
“We’re starting to see exciting new techniques, like nanopore sequencing –where DNA is transported through protein nanopores and changes in electric current are read as different bases. It’s really quick (and the device is portable) so could be used out of the lab during a disease outbreak like Ebola. We also now have single cell sequencing, which can sequence RNA and look at the difference between cells of the same type, and spatial transcriptomics, which allows you to sequence RNA in a 2D context.
“But one of the biggest challenges now is access and price – we’ve seen this come down a lot but sequencing is still too expensive for all labs to have. Data storage is also a big issue – the more we’re able to sequence, the more we need to store!”
Genetic modification – altering the building blocks of life
“We’ve understood that we can selectively breed for a while now, whether that’s introducing new dog breeds or improving food crops. But this was random and relied on mutations arising spontaneously. It wasn’t until they started to understand what a gene was and then when the structure of DNA was discovered that scientists were able to
“Fast-forward twenty years and in 1981 the first genetically altered animal model was created, a transgenic mouse, where a one-cell embryo had been microinjected with a foreign gene from a rabbit. But again, this was not hugely specific.
“The big shift came with CRISPR Cas9 in 2012, the same year I started university! CRISPR can be thought of as ‘molecular genetic scissors’ – it’s much more precise as it can be paired with a guide to splice a specific point in DNA. CRISPR is being tested for so many uses, from genetically modified animal models to biofuels or even making beer less bitter!
“A lot of work happening in the future will be about refining CRISPR techniques, and another exciting new area is prime editing, which acts on a single base rather than a base sequence like CRISPR, and is already being used in treatments for diseases such as sickle cell anaemia.
“But there are ethical issues to consider around the use of gene editing in medical therapeutics and in humans. It’s something we’ve dedicated a whole public exhibition to so that members of the public can debate these issues.”
Structural biology - turning up the resolution on the structure of molecules
Qu Chen is a senior laboratory research scientist in the Structural Biology team. She supports the cryo-electron microscopy pipeline, running collaborative projects while helping other teams across the Crick to use cryo-EM.
“In the 1950s, X-ray crystallography was the main way to see the 3D structure of molecules. This involves crystallising a molecule and using X-rays to show the structure. It’s great for small macromolecules, but there are limitations with using it for bigger macromolecules. A similar technique, X-ray diffraction, was used in the1953 papers to uncover the structure of DNA.
“In the 80s, cryo-electron microscopy was developed. The concept is to freeze a sample into a thin layer of ice and capture it using electrons to form images. With cryo-EM, the physiological state of the molecules is maintained. It was first used for big molecules like viruses, but with the resolution revolution in the 2010s, cameras became so much more sensitive and computers more powerful, so we were able to see much smaller molecules.
“A good example is the ribosome, the site where proteins are made. Researchers had been trying to solve the crystal structure of the ribosome since the 1970s, but because it’s big and flexible, it’s hard to crystallise, so it wasn’t until the 2000s that the first structure was produced using x-ray crystallography. But using modern cryo-EM, it only takes a few days to get a similar quality structure, as cryo-EM is a more suitable approach for this type of molecule.”
“Today, cryo-EM and X-ray crystallography are complimentary techniques to understand the structure of molecules. And we’re starting to be able to do even more, like cryo-electron tomography, where you can directly study macromolecules inside cells."
“When I first saw the beautiful simplicity of the DNA molecule, I was fascinated. It has answered so many questions about life, but there are still many more questions to answer, from how all the processes in genome maintenance and expression interact with each other to how epigenetics influences disease.
“The revolution in technology means that human genomes can now be read so much faster and has enabled us to make precise edits or understand the structure of molecules with immense precision. I’m looking forward to seeing how much more we can discover.”