The blueprint of life

The deoxyribonucleic acid, or DNA for short, is the blueprint of life. It contains all the genetic information required for complex organisms to be alive and to sustain life. Now, we've known since the 1800s, with Mendel and Charles Darwin as well, to some extent, that there are some genetic traits in us that can be preserved and passed to future generations. But it was not until the 1940s that people started to ask the question of where those genetic traits are stored.

Originally, they were thought to be stored in proteins. Then slowly, people started to realize that perhaps they were stored in this deoxyribonucleic acid, or DNA.

© Circli

That led slowly to several teams trying to race each other to discover the structure of DNA. And since 1953, since the Watson-Crick paper, we now know that DNA is made as a double helix – two strands of nucleotides. These nucleotides can be A, T, C, G – or adenine, thymine, cytosine and guanine – which are placed one after the other, giving unique sequences along our genome, along our DNA. They encode the genes, the blocks of information that are required to encode genetic traits.

Evidence for the double helix

One of the first x-ray images from DNA was taken by Rosalind Franklin.

© Raymond Gosling

You see essentially the diffraction patterns of the x-ray being scattered by the structure of DNA onto the plate. What scientists used to do – among them Rosalind Franklin, Watson and Crick, and others – was try to understand how the diffraction pattern was originating from a structure.

For instance, people like Linus Pauling, a few years before Watson and Crick, suggested a structure for DNA which was wrong originally, but it got closer and closer to what we now know is the double-stranded helix that is quite famous and that a lot of people are familiar with.

DNA inside cells

In this image, you see the extreme level of packaging that DNA is under inside the living cell. So in this E. coli – Escherichia coli is a bacterium – it's a single cell and contains its whole genome in that cell.

© Guillaume Le Treut

In this particular picture, what you see is that the DNA has exploded. The bacterium has been lysed – has been essentially pierced – and the DNA is all exploded out.

What you should imagine is that all that DNA is compacted, confined, within that little cell that was originally the live bacterium. To me, the first thing that everyone should notice is how extreme and unimaginable the level of compaction the DNA is experiencing inside the bacterium is. This picture really tells a lot about the fact that DNA is not simply this abstract object that contains genes and genetic information. It is really a physical object, almost like a physical rope that you have to stuff into a bag – let's say, into a membrane – to make a living thing, to make a living organism.

Naked DNA

DNA in bacteria is stored so-called naked. It is packaged using proteins but is not packed into chromatin as in eukaryotes, which means higher-order organisms essentially. So eukaryotes are us. We are eukaryotes in the sense that we have a cell, and it contains a nucleus. The nucleus of the cell contains the genome.

© Richard Wheeler via Wikimedia Commons / CC BY-SA 3.0

In eukaryotes, DNA is packaged into what you see in this image. It’s wrapped around histones, which are proteins. The complex of DNA and histone is called the nucleosome, and it's packed together again into a fiber. The fiber is called chromatin. This chromatin is then itself folded into three-dimensional shapes in the cell nucleus.

What is really interesting, and I'm really passionate about this, is that in the past ten years, people are starting to discover that the shape, the way chromatin is folded in the nucleus, affects the way genes are expressed. So in eukaryotes – in plants, in animals, in humans – there are about 20,000 genes. Obviously, it depends on the species, whether it's a plant or an animal, but it's about the order of magnitude of genes: 10,000 to 20,000 genes.

Not all of them are active at the same time. This is an important point to make, in the sense that DNA, and in particular chromatin, is not a passive book. The cells in a complex organism like us need to express different genes because they need to execute different functions. For instance, a muscle cell is different from an eye cell or a kidney cell or a liver cell. They all have to express different proteins, and to express different proteins, they have to have different genes active – different patterns of genes that are active.

To understand what determines the patterns of genes, we have to look at genome organization: how the genome, how the DNA and chromatin are organized inside the cell nucleus. This is what many groups are doing, and we are also contributing a little bit in this field.

Reading the genome

Understanding genome organization, in some sense, is key to understanding cell health and disease. When I was saying that the genome, the DNA, is not a passive book, there are two aspects to this. One is that this book – some pages of this book – are read by different cells. When a healthy cell becomes a cancer cell, for instance, the pages of that book that are read – or the genes that are active – change.

© The National Institutes of Health

So there is a change in the transcription pattern – in which genes are transcribed into RNA and then translated into proteins – depending on the cell state and the cell health as well. There is an interplay, which is very intimate and delicate and subtle. In some sense, it's very difficult to understand the interplay between which genes are active and how that part of the genome is folded within the nucleus of the cell.

DNA environmental response

The DNA and the genome respond to environmental clues. For instance, plants have a different immune response than us. What happens is that when plants are attacked by pathogens, cells can sense the presence of these pathogens using sensing proteins. These sensing proteins act to change the transcription pattern itself.

So the DNA transcription pattern changes depending on whether the cell is being attacked. When the cell senses this attack by the pathogen, by the attacker, it starts to create defense proteins. These defense proteins then defend the cell against the pathogen. Or they could induce cell death. For instance, when you see yellow spots on green leaves, sometimes it's because the spot of cells decides to die to save the rest of the plant.

© Wikimedia Commons

Then my question was: why doesn't the cell always produce these defense proteins against pathogens? This is because it would be too energetically costly. If it produced these proteins all the time, it would affect growth. It would reduce the growth of the plant. The plant has to decide whether to grow or to defend itself.

This is also another example of how active our genome is, and of complex organisms. It changes in response to what happens nearby. The big challenge in the field of genome organization is to try to understand not only how a static snapshot of how it is organized inside the cell at a given time, but how it changes over time, so the dynamics of the genome inside the cell. In some sense, also how the entanglements and the structure of this chromatin – how the folding of this chromatin – affects the behavior, the response to attacks, or the changes in gene expression when the cell goes from healthy to diseased, for instance.

The DNA race

The history of DNA discovery has been a very tumultuous one. Clearly, in the 1930s, 40s and then 50s, there was a lot of effort and a lot of teams that were interested in resolving protein structures. Then some of the teams also started to use the same techniques – x-ray crystallography – to resolve the structure of DNA.

There were several teams in the UK. There were the Cambridge teams. There were Watson and Crick. There was Rosalind Franklin with Wilkins in London. There was Max Perutz as well in Cambridge, and Linus Pauling in Caltech with Max Delbrück. They were all trying to understand the structure of DNA. From what you read in the books, it really felt like a race to see who got there first.

I remember reading that when Linus Pauling came up with the first prediction of the DNA structure, which was wrong – he predicted a triple helix, with some also other incorrect predictions about where the phosphates were – Bragg here in the UK was quite upset and started to put pressure on the researchers to get there first, to try to get to the correct structure first.

© Marjorie McCarty

This is how Watson and Crick got hold of the DNA crystal structure that was generated by Rosalind Franklin in London and that was still unpublished at that time. Watson and Crick got hold of this picture and managed to come up with the correct structure.

To me, whenever I read this story, it always feels very current. It feels like it's something that could happen even now, in the sense that academia often is idealized from the outside. But in truth, what happens inside often feels like a race – who's the first team to get to a certain answer, a certain prediction. It's not always about healthy competition, and sometimes it seems that it is done to fuel the ego of some people rather than out of genuine passion for discovery and science.

Lessons from DNA history

It teaches us that we should try to keep the focus on the science, on the evidence. Leave as much as possible ego outside of the equation and focus on what is important. It also teaches us positive things. For instance, it teaches us that science is really an interdisciplinary effort.

© Smithsonian Institution, restored by Bammesk

Something I haven't mentioned – but I think it's really important – is that the discovery of DNA was really interdisciplinary. There were biologists, physicists, chemists, crystallographers from the start. They were all together. This absence of barriers between disciplines was there then, and it is here now, but is not actually reflective of how many universities and how many funding bodies are structured.

Many funding bodies are still very sectorial, and they talk about remits of their science. But this is clearly outdated. It was outdated even in the 1950s. We have to rethink a little bit the structure of universities and funding bodies. It's a very difficult task, and I think people are trying to do it, but it's a work in progress.

This barrier between disciplines is not there. Science is just one. Scientists have to have the freedom to communicate on the same level and freely between disciplines without feeling these artificial barriers that are put there just for admin purposes.

DNA’s physical structure

© National Human Genome Research Institute

One misconception that I would like to fight is the idea that DNA is only an abstract object that contains genes and genetic information. It is also a physical structure. It's a double helix with the Watson-Crick base pair rules. The fact that it has this structure makes it an active participant in deciding which genes are expressed, and therefore how cells behave, and therefore how we are built as complex organisms.

It's a very important concept that I think is not understood in the general public – that it is really a physical object that contributes to its own function.

Editor’s note: This article has been faithfully transcribed from the original interview filmed with the author, and carefully edited and proofread. Edit date: 2025

Discover more about

DNA and its structure

Watson J. D. & Crick F. H. C. (1953).Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid.. Nature volume 171, pages737–738

Michieletto, D., Orlandini, E., & Marenduzzo, D. (2016).Polymer model with epigenetic recoloring reveals a pathway for the de novo establishment and 3D organization of chromatin domains. Physical Review X, 6, 041047.

Eeftens, J. M., Kapoor, M., Michieletto, D., et al. (2021). Polycomb condensates can promote epigenetic marks but are not required for sustained chromatin compaction. Nature Communications, 12, 5888.

Michieletto, D., Lusic, M., Marenduzzo, D., et al. (2019). Physical principles of retroviral integration in the human genome. Nature Communications, 10, 575.

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