Tag Archives: DNA

A rogue cell blooms into a kaleidoscope of cell types. Credit: Martin Nowak, Bartek Waclaw and Bert Vogelstein

The Evolution of New Cancer Treatments

Could Charles Darwin help us to fight cancer? The answer is an emphatic yes according to an Anglo-American team which today unveils eerily beautiful videos that model the evolution of a tumour in three dimensions.

In one set of computer simulations, a rogue cell blooms into a kaleidoscope of cell types, then melts away when treated with a cancer drug, only to blossom once again with renewed vigour into deadly and malignant masses of billions of cells.

A rogue cell blooms into a kaleidoscope of cell types. Credit: Martin Nowak, Bartek Waclaw and Bert Vogelstein

A rogue cell blooms into a kaleidoscope of cell types. Credit: Martin Nowak, Bartek Waclaw and Bert Vogelstein

Cancer is marked by a breakdown of cooperation between cells in the body, when one of the body’s 200 or so cell types develops mutations – changes in their DNA – that put the cell’s own interests above the greater good of the body.

By shrugging off the controls that keep the rest of our body in check, tumour cells divide willy-nilly, picking up new genetic changes along the way so they can evolve to resist drugs, or grow faster, for example. As a result, even a single tumour can contain utterly different genetic mutations in the cells at one end, compared with cells at the other.

But because cancer cells are distorted versions of normal cells in the body, they are hard to target and destroy without causing damaging side effects. Because cancer is marked by its rapid growth doctors have, for example, used drugs that are toxic to all dividing cells in the body, causing side effects such as hair loss, nausea and so on.

Recent years have seen the development of drugs that target cancer cells with specific mutations. These drugs shrink tumours during the first months of treatment but the cancer cells often become resistant as new mutations help to outwit the drugs, and the disease returns.

Now the collaboration between Harvard, Edinburgh, and Johns Hopkins Universities has come up with a mathematical portrait of the evolution of solid tumours of the kind found in the breast, ovary or colon.

The new work, published today in the journal Nature, is a joint project by a team that includes Bartek Waclaw a physicist and computer wizard at Edinburgh, the distinguished cancer researcher Bert Vogelstein of Johns Hopkins, and Martin Nowak, Director of Harvard’s Program for Evolutionary Dynamics, who has spent decades trying to put biology on a mathematical basis, along with his colleague in Harvard University, Ivana Bozic.

Although biologists traditionally complain that disease processes are too complex to boil down to mathematics, Nowak believes the new model can explain various features of cancer, from why cancer cells share a surprising number of mutations in common, to why tumours spread and become resistant to anti-cancer drugs.

The new mathematical model captures the complex way that DNA mutates in different tumour cells, which makes some cells more suited to the environment than others, and how cancer spreads. Until now, these have been modelled separately. “Most previous efforts counted the number of cells with particular DNA changes but not their spatial arrangement,” says Nowak. “Now we can model both the genetic evolution and the 3D growth of a cancer.”

One of the new insights to emerge is that cancer growth depends greatly on the ability of tumour cells to cells to divide if they have sufficient space. This means the tumour grows slowly unless cells are able to move to find enough room. “Cellular mobility makes cancers grow fast, and it makes cancers similar in the sense that cancer cells share a common set of mutations,” says Nowak. That, he thinks, is why drug resistance rapidly evolves.

In the video, similar colours denote similar mutations and – as the tumour grows – they remain clustered together, as also shown by experiment. Of the billions of cancer cells that exist in a patient, only a tiny percentage – about one in a million – are resistant to drugs used in targeted therapy. When treatment starts, the video shows how non-resistant cells are wiped out – but the few resistant cells quickly repopulate the cancer.

There is another insight to emerge from focusing on cell movements within the tumour: they go on to evolve the ability to spread throughout the body, to metastasize, which is usually what makes cancer deadly. Nowak says: “The ability to form metastases is a consequence of selection for local migration, that is Darwinian processes favour cells with the ability to move around the body.”

These insights, which are a ‘beautiful confirmation of what is seen in experiments,’ do not provide a ‘miraculous cure,’ said Bartek Waclaw, “However, they do suggest possible ways of improving cancer therapy.”  The video shows how cancer cells switch to a state when they can deform and move around and, he says, treatments that hinder these small movements of cancerous cells could help to slow progress of the disease.

The attempts through history to understand and combat diseases such as cancer can be found in the Science Museum’s medicine collections, which contain over 140,000 objects. The museum is now developing major new Medicine Galleries to showcase thousands of objects with initial leadership funding from the Wellcome Trust, the Heritage Lottery Fund and the Wolfson Foundation.

The galleries will open in 2019, transforming much of the first floor of the Museum. In preparation, Glimpses of Medical History and The Science and Art of Medicine will close on 20th September. However, you will still be able to see highlights from the collection in a new exhibition, Journeys Through Medicine: Henry Wellcome’s Legacy, opening on Thursday 1st October. Further items can also be seen at the Wellcome Collection and explored online via our Brought to Life: exploring the history of medicine. These collections are of enduring interest because medicine is where science collides with life.

By Roger Highfield, Director of External Affairs and coauthor with Martin Nowak of SuperCooperators, Beyond the Survival of the Fittest: why Cooperation, Not Competition, is the Key of Life

Obituary: Fred Sanger (1918 – 2013)

Director of External Affairs, Roger Highfield, remembers Nobel laureate Fred Sanger.

The biochemist and Nobel laureate Fred Sanger would joke that ‘I am all right at the thinking, but not much good at the talking.’ Despite his huge influence, Sanger also once said that: ‘I am not academically brilliant.’

Frederick Sanger. Credit: Wikipedia

Frederick Sanger. Credit: Wikipedia

I met him for the first time among the audience of a Wellcome press conference in London and, not once in our chat about human genomics, did he let slip who he was and the landmark contribution that he had made to the field.

In fact this modest man was one of the greatest innovators of all time with his emphasis on developing new techniques, notably DNA sequencing, the ability to read the genome, or genetic recipe, of an organism while working at the Medical Research Council’s Laboratory of Molecular Biology in Cambridge.

Ian Blatchford, Director of the Science Museum, commented on hearing news of his death that  Sanger was a ‘giant in genetics, who had an astonishing capacity to crack some of the most challenging problems in biology. His passing marks the end of an era in modern genetics.’

The American genome pioneer and synthetic biologist, Craig Venter of the J. Craig Venter Institute in Rockville and La Jolla, said on hearing the sad news: ‘Fred Sanger was one of the most important scientists of the 20th century. He twice changed the direction of the scientific world, first with the sequencing of insulin, proving that proteins were linear strings of amino acids and second with his then new method of sequencing DNA, which led to the field of genomics. His contributions will always be remembered.’

Most sequencing performed for the past decades is a direct extension of the methods that were pioneered by Fred Sanger. He unveiled his first partial DNA sequence in May 1975 and went on to deliver the first complete determination of the sequence of a DNA molecule: the 5375 ‘letters’ in the genome of a bacterial virus called phi-X174.

This machine, developed in 1987, uses the Sanger method for DNA sequencing. Credit: Science Museum

This machine, developed in 1987, uses the Sanger method for DNA sequencing. Credit: Science Museum

The DNA reading method that Sanger developed in Cambridge with Alan Coulson required the manufacture of lots of copies of the DNA molecule using an enzyme called DNA polymerase. For the polymerase to replicate DNA it needs DNA building blocks – molecules called nucleotides – which correspond to the four ‘letters’ of the genetic alphabet.

The enzyme reads from each end of the original molecule to make new copies. For sequencing, Sanger added another ingredient: molecules called ‘terminator nucleotides’, each radioactively-labelled, which are so named because they stop the polymerase when they are incorporated in the growing copy. As a consequence, the enzyme incorporates a terminator in the growing DNA chain, halting the process and marking the end of the growing chain with a radioactive molecule as a full stop.

Because this interruption occurs at any stage of the process of copying vast numbers of DNA molecules in the test tube, a mixture is produced of DNA fragments of varying lengths, each finishing with a radioactively-marked C, G, A or T, depending on which base had been labelled.

An electric field was used to drive these fragments through a gel to separate the DNA molecules according to their size and reveal the sequence: the largest pieces of DNA take more time to migrate through the gel. Because the radioactive label on all four terminators produces the same black mark on an X ray film, Sanger had to carry out four individual experiments, one for each different letter of the code, on four adjacent tracks on the same gel. When the genetic fragments separate, one track shows the DNA fragments that end with a C, one those that end with a G and so on.

Then Sanger and his colleagues studied the film, starting with the first band from the four letter tracks, moving to where the next closest band appeared. In this way, they could read the digital recipe of life. If the first, smallest, piece of DNA was in the C track, for example, then C was the first letter. If the next black mark was in the A track, then an A followed.

Sanger sequenced the 17,000 or so letters of DNA in the human mitochondrion, the energy factory found in our cells. This feat can be regarded the first human genome project. He won the Nobel prize for this work in 1980 but it was far from his first major award.

Frederick Sanger used this equipment to study the structure of insulin by electrophoresis in the 1950s. Credit: Science Museum

Fred Sanger used this equipment to study the structure of insulin by electrophoresis in the 1950s. Credit: Science Museum

He had been given his first Nobel prize in 1958, for his research on the structure of proteins, when he worked out the order of the 50 or so amino acids that make up the insulin molecule. This work revealed how DNA specified linear strings of amino acids in proteins, and that proteins were not agglomerations of closely-related substances, as many had thought in the first half of the 20th century, but were indeed a single chemical.

The world has lost a gene genius.

Discover more about genetics in the Science Museum’s Who Am I? gallery.

Crick and Watson’s DNA molecular model from 1953. Image credit: Science Museum

1950s: Double Helix

Each day as part of the Great British Innovation Vote – a quest to find the greatest British innovation of the past 100 years – we’ll be picking one innovation per decade to highlight. Today, from the 1950s, Double Helix: Discovering the structure of DNA.

Almost all frontiers of biological research in the 21st century owe their origins to the work of two Cambridge scientists (James Watson and Francis Crick) and their contemporaries at King’s College London (Rosalind Franklin and Maurice Wilkins).

Watson and Crick’s collaboration began in 1951, drawing on a range of evidence – including chemical techniques and X-ray crystallography – to determine the elusive structure of deoxyribonucleic acid (DNA). A breakthrough arrived when Watson was shown Rosalind Franklin’s X-ray crystallography photos of DNA, which clearly suggested a helical structure. As Watson wrote in his memoir: ‘The instant I saw the picture, my mouth fell open and my heart began to race’.

Crick and Watson’s DNA molecular model from 1953. Image credit: Science Museum

Crick and Watson’s DNA molecular model from 1953. Image credit: Science Museum

Understanding the structure of DNA, particularly how a sequence of simple nucleotides (A, C, G & T) can encode genetic information, has revealed ‘the secret of life’ – as Francis Crick announced in a Cambridge pub in 1953. A decade later, Crick, Watson and Wilkins were awarded the Nobel Prize for their work (Franklin missed out as Nobel prizes are not awarded posthumously).

Listen here to broadcaster and writer, Judith Hann, explain why deciphering the structure of DNA should get your vote, and click here to see a reconstruction of Watson and Crick’s DNA model in the Museum.