Family Tree of Breast Cancer

Minding my language

There may be the odd soul out there who has now read Betrayed by Nature and spotted that, just once in while, there’s some very unscientific language. The select band of blog followers (I think of them as The Few) will have noted the same thing (in ‘Touching base with our rellos’, for example). The odd ‘astonishing’ slips out. An occasional ‘incredible’ creeps in – we’ve even been ‘stunned’. “What on earth is he on about?” you might wonder. Scientists aren’t supposed to talk like that. For them it’s measured tones, words weighed with care and, of course, they do sitting on spiky fences with such aplomb you might conclude they’re a bit on the kinky side.

It’s a fair cop

It’s all true. But here’s my defence. Of late, when you might think I’ve been a shade ott, it’s almost always because I’ve been talking about sequencing DNA. Here the events of the last few years have been truly breathtaking. In all respects, I would maintain, they rank among the most awe-inspiring in the history of science. There are two reasons for this belief so let me share them with you, prompted by yet another absolutely remarkable piece of work on cancer that has just been published.

Two astonishing things

First is the technology. Today’s machines can carry out 100s of millions of separate sequencing reactions at the same time (just say that slowly). In the jargon it’s ‘massively parallel sequencing’. How they work matters not here but the ingenuity and engineering that make it possible to find the order of bases in DNA at such speeds is simply mind-boggling.

Second is the outcome. The speed of these gadgets means that the entire DNA sequence of an individual can be obtained in a day or so and that tumours are now being sequenced on an industrial scale. That’s being done to obtain a picture of the sets of mutations that define sub-sets of the major cancers.

The Family Tree of One Individual Breast Tumour

You can’t have too much of a good thing

But these advances mean you can do something else: sequence the same tumour again and again – hundreds of times. Why would you want to do that? The answer is that tumours are a real mixture – a gemisch of groups of cells (called ‘clones’), each descended from a single common ancestor so that the cells in a clone are genetically identical. So, if you really want to know what you’ve got, you need to be able to detect individual clones and the only way to do that is to sequence over and over again until you can get reliable data for the rarer DNA codes that come from smaller clones. That’s just been done for one individual breast tumour and the result is an evolutionary tree showing how the cancer had developed from the fertilized egg to the point it was diagnosed.

The major clones that made up the tumour when it was diagnosed (B, C and D) all descended from a predecessor (A), the most-recent common ancestor. Tens of thousands of mutations went into making A. Thousands more accumulated to form B, C and D. The arrows extending from B, C and D represent the emergence of further clones in what is a continuing, dynamic process. Their record is written in their genomes – a book of progress reports.

One more pretty remarkable thing

In the UK and the USA about 12% of women will be diagnosed with breast cancer. In 2008 world-wide 458,503 women died from the disease and we still have no treatment that is specific in targetting only the tumour cells. It is, therefore, really staggering that improvements in surgery, radiotherapy and drugs in the last 60 years has seen the 5-year survival rate go from 40% to over 90% for white American women and to about 80% in the UK.

Despite this progress, the ideal for every cancer would be to use the family tree to identify the key driving mutations from the tens of thousands in the major clones and then use cocktails of specific drugs to zonk them. At the moment we are a long way from having such an armoury but the current rate of progress in defining tumours at the molecular level, driven by the fabulous technology of sequencing, means that at long last we can proceed on a rational basis, rather than by the time-honoured method of trial and error.

Reference

Nik-Zainal et al., The Life History of 21 Breast Cancers, Cell (2012), doi:10.1016/j.cell.2012.04.023

http://libsta28.lib.cam.ac.uk:2057/science/article/pii/S0092867412005272

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And a photo!

Cambridge University added this picture to their website review of Betrayed by Nature. It shows human endothelial cells in culture labelled with three different fluorescent molecules. Publishers, unfortunately, aren’t too keen on colour pix – so my assertions in the book about the stunning things you can see down microscopes aren’t backed up by images like this!

For the enthusiast: cell nuclei are blue, the green fibres are actin and a protein called von Willebrand factor (only made in these cells that line blood vessels)  has a red label. The cell at bottom right is on the point of dividing. Photo by Emily Hayes.

A Word From Cambridge University

Everything we think we know – and know we don’t know – about cancer

A book written for the general reader, Betrayed by Nature: The War on Cancer by Dr Robin Hesketh, sets out in plain English what goes wrong in our bodies when cells begin to replicate in an abnormal manner, and what science is doing to address the disease that kills seven million people every year.

For 20 years or so Dr Robin Hesketh, Senior Lecturer in the Department of Biochemistry at Cambridge University, thought about writing a book.  What he had in mind was one “that explained in the most simple way everything we think we know about cancer”. But he put it off, concentrating instead on experiments aimed at finding ways of stopping tumours growing and teaching Cambridge students about cells and how they signal to themselves and to each other. Then, one wet Sunday in 2008, he sat down at home and wrote the first words of Betrayed by Nature: The War on Cancer (Palgrave Macmillan, 2012).

Everything we think we know about cancer turns out to be quite a lot. We know that one in every three or four of us will get cancer during our lifetime – but that some of types can now be treated with very high success rates. We know that cancers are abnormal growths of cells – neoplasms – and that we’ve all got them in some form. Moles are unusual clumps of cells but are – almost always – unthreatening. We know that cancers can subvert our immune system, not only leaving us vulnerable to infection, but turning it from protector to traitor, giving succour to the neoplasm that can kill us. And we know that the lethality of these growths comes mainly from their acquiring the means to move home and, in wandering around the body, find a new locale in which to settle (a process known as metastasis).

Betrayed by Nature starts with a stroll through the history of cancer. As early as 1,600 BC the Egyptians were aware of conditions for which there was no treatment. Around 400 BC Hippocrates came up with the word carcinoma to describe tumours with a high density of blood vessels. Some 600 years later Galen, another Greek, is credited as the first person to use the word cancer (Latin for crab).

It wasn’t until the 18th century that physicians began to link cancers to occupation and lifestyle.  In 1713 Bernardino Ramazzini noted that cervical cancer was rare in nuns yet they were prone to breast cancer. A few years later Percival Pott concluded that sweeps (many were boys who were sent up chimneys naked) developed cancer of the scrotum as a result of soot lodging in the folds of skin. And then in 1866 Paul Broca, having studied his wife’s family tree, became the first to suggest it might be possible to inherit breast cancer. Even before those observations, the 17th century pioneer Robert Hooke – a polymath whose inventive mind embraced physics, astronomy and the first blood transfusions – had identified the cell as the basic unit of life, laying the foundations for the field of cell biology.

Hesketh’s historical saunter leads us to the modern era of molecular biology. Launched by the revelation of the double helical structure of DNA in 1953, this field has seen an explosion of knowledge as the basic machinery of life has been unveiled. At its heart is the instruction code enshrined in DNA, in humans a sequence of three thousand million bases, and ‘DNA makes RNA makes protein’ has become ‘the central dogma’. With this has come the demonstration that thousands of diseases arise from corruptions in the code that are manifested in abnormal proteins. A well-known example is cystic fibrosis, an ultimately fatal condition caused by a mutant form of just one protein made in the lung.

Cancers too are mutation-driven diseases but with two crucial differences. The first is that cancers are driven by not one but several mutations acting in concert. As tumours develop they accumulate thousands of random mutations from which groups of perhaps half a dozen provide the driving force. The second is that the effect of ‘driver’ mutations is to cause cells to reproduce themselves abnormally. Many cells in the body replicate rapidly while some scarcely replicate at all after initial development is complete, and others can be ‘turned on’ when required, for example to repair injured tissue. The problem caused by cancer mutations is that they make cells multiply (in cell biology, multiplication is division) either too rapidly or at a time when, or in a place where, they shouldn’t.

Hesketh paints a picture of the infinity of flexible shapes that proteins can form and then illustrates the four major types of mutation that can act as cancer drivers. From this, the story moves to the effect of such mutants on the way cells behave – how normal cells are seduced into ignoring signals they should respond to, how cancer cells avoid suicide signals so that they survive with their mutant accelerators and defective brakes, adjusting their metabolism and co-opting nearby normal cells to promote their extravagant lifestyle, ensuring that survival and expansion of the tumour dominates. And then finally and fatally, we discover what happens when cancer cells spread in the usually fatal diaspora.

Betrayed by Nature addresses the unspoken question ‘if cancer is essentially so simple, how come it’s killing seven million people a year and the 12 million new cases in 2008 is set to become 15 million by 2020, when 30 million people on the planet will have cancer of some sort?’. Part of the answer is that we persist in doing things we know will get tumours going: sunbathing without protection (especially fair-skinned people), smoking (despite trends in some countries, the figure of over five million a year that tobacco use kills now, that’s one every six seconds, will rise to over eight million a year by 2030), eating poor diets and getting fat. On top of this, there’s the fact that we’re all living longer – and the longer we stick around, the more likely we are to develop cancer. In the Bronze Age the average lifespan was 18 years. Now world-wide it’s 66 and in the UK over 80 – facts that have the curious effect of making the cancer mortality rate in India (average life expectancy 64) half that of the UK.

The other – and more complicated – part of the answer lies in DNA and its extraordinary flexibility. The random game of chance is that life means that the odds are heavily against a fertilized egg making it into a human being. When it does so it will have encoded in its DNA millions of variants, not only making each of us different to one another (the basis of DNA ‘fingerprinting’) but also giving us an individual molecular canvas upon which the layering of subsequently acquired mutations will inevitably lead to cancer – if we live to be 140. The cancers that emerge are so highly individual that each is unique. Each tumour has a different genetic make-up, even though historically pathologists have classified them into distinct categories.

The astonishing individuality and complexity of each tumour is being revealed in molecular detail by current DNA sequencing methods and the final instalment of this saga is all about what Hesketh now regrets describing as “the greatest revolution in the history of medicine” in the book. He comments: “I should have substituted ‘science’ for ‘medicine’ because the technical advances that have occurred since the human genome was first sequenced in 2003 have already changed how we think about cancer and how we treat it and in the end they will affect everyone on earth.” The chapter ‘Let’s Sequence Your DNA’ notes that when the project to sequence the human genome was launched at the end of the 1980s the cost estimate was $1 per base: the current figure is one millionth of that—10,000 bases for one cent. The first sequencing machines in the early 1980s managed 10 kilo bases (10,000 bases) a day; the present rate is heading towards 100 million kb per day. So the cost has gone down by a factor of one million and the speed has gone up by 10 million.

All of this means that individual tumours can now be sequenced before treatment strategies are drawn up. For a number of the major cancers, sequencing has shown that tens of thousands of mutations accumulate as the tumours evolve in a process that Hesketh likens to ‘dynamic Darwinism’ as changes in DNA that confer a growth advantage permit clones to expand and dominate. The complexity of these mutational patterns is bewildering and it is almost beyond belief that a cell can survive such ferocious assaults on its genetic integrity, yet alone that a clone may emerge with the power ultimately to overwhelm its host.

A new vista in medicine is opening up, one that for cancer has already identified the major driving mutations and thus provided focal points for the development of new drugs. In parallel with the sequencing revolution, major strides are being made in ways of visualising tumours so that they can be detected with greater sensitivity and also that the effects of drug therapy may be followed. In addition, the progressive identification of molecular ‘biomarkers’ present in circulating blood will permit tumour detection at much earlier stages than is currently possible. These efforts are driven by the fact that surgery remains the first line of defence. More than 90% of cancer deaths come from metastasis. If they can be treated before they spread, by surgery and radiotherapy, the success rates are very high.

Amazing though the developments of the last ten years are, as is always the case in science, they build on what has gone before and Betrayed by Nature highlights the tremendous strides made in the second half of the 20th century. The pioneering work of Sidney Farber at Harvard in the 1940s produced remission of childhood leukemia. Since then other very effective treatments have evolved, as illustrated by the progressive rise in five year survival rates for breast cancer and prostate cancer to over 85% and almost 100%, respectively. One of the greatest triumphs has been the development of vaccines that are essentially 100% effective in preventing cervical carcinoma by blocking viral infection that is the cause of almost all these cancers.

The optimism in Betrayed by Nature derives from the evidence that the era we are entering offers not only the possibility of making an impact on cancers that have remained intractable but that, as detection is refined and the stock of specific drugs expands, we may even contemplate the replacement of surgery by highly effective chemotherapy. But Hesketh also has some simple messages that speak directly to today’s readers. “You can avoid a lot of things in life if you really want to: football, hamburgers, sex … but you can’t avoid cancer at least coming very close to you.” As for what we can do to maximise our chances of staying well, he says: “Don’t smoke – but if you do, give up – it’s not too late!” “Eat sensibly and do a bit of exercise” And he adds: “Men especially, if you think something’s wrong, follow JBS Haldane’s advice: don’t be macho – go and see your doctor.”

Betrayed by Nature: The War on Cancer by Robin Hesketh is published by Palgrave Macmillan, 2012.

Don’t Read This!!

Now here’s something I bet you’ve never thought about. Well I certainly hadn’t when I stepped outside the boundary of ‘science’ and into the world of ‘pop sci’ – aka Betrayed by Nature.

Professional evisceration

To get sciency stuff published you have to endure the dread process of ‘peer review’. Your paper is sent to experts who apply their giant brains, formidable grasp of the subject and sadistic natures to a completely impartial assessment of whether it is of sufficient merit to appear in whichever journal you have favoured with your attentions. Or, put another way, it gets put through a mincer that takes fiendish delight in dissecting every syllable, making ‘suggestions’ that amount to a total re-write and demanding a further series of experiments (to ‘solidify’ the data) that would see you past retirement, if not into the beckoning abyss beyond. If, by combining grovelling submission, bartering, and deviousness you finally get the thing into print, what happens next? Nothing. Not a squeak. The vast majority of papers disappear as surely as if dropped into the Mariana Trench in a lead-lined box. Just occasionally, if a few of the co-authors have Nobel Prizes, you might find your opus clambering up one or another citation index, meaning that some other bunch of numpties have mentioned it in their own feeble scribblings – doesn’t mean they actually read it, of course. And that’s it.

Pop in public

But out in the real world ‘pop’ stuff comes out – and then gets reviewed – so it’s like writing chick-lit (I’ve no idea what that is but I quite fancy having a go). And the critics turn up from all over the place. Their views get emailed to you by well-intentioned friends, someone in the coffee queue regales you (“just seen ….”) or you stumble over one when your surfing fingers inadvertently hit ‘sci reviews’ instead of ‘sex reviews.’

So Monty Python was wrong – you do expect The Spanish Inquisition – that any minute you’ll be dragged naked through the streets of Cambridge – well, emotionally at least. So, after all that, a lady friend has told me to be a man (very naughty to have peeked) and to bravely blog reviews received.

You have been warned!

Reviews of BETRAYED BY NATURE The War on Cancer by Robin Hesketh Palgrave Macmillan 272 pp. £16.99 (2012)

1.  William Hanson, MD, author of The Edge of Medicine: Dr. Hesketh brings an expert’s easy familiarity and depth to this comprehensive, at times almost affectionate, look at a deadly adversary. He tells us what cancer is, what causes it, what we can do to prevent it and how we are systematically battling the disease on many fronts.

2.  Kirkus Reviews (The World’s Toughest Book Critics) 1 March 2012:  Informative, optimistic tour of the science of cancer: Hesketh (Biochemistry/Cambridge Univ.), familiar to lay audiences from BBC radio and TV, opens Part 1 with a capsule history of cancer, ranging from papyrus records of ancient Egypt to the scientific breakthroughs of the 21st century. He follows with a look at the distribution of different types of cancers around the world and what the data suggests about cancer’s causes. Matters get technical in Part 2, but the author assumes little previous knowledge on the part of readers; he takes time to explain DNA, RNA, genes, chromosomes and how some genes mutate into cancer genes. In Part 3 he tackles cancer cells and the behavior of tumors. Throughout Parts 2 and 3, relatively simple diagrams and some black-and-white photographs help to clarify the technical discussions. For most readers, the final section – “Where Are We? Where Are We Going?” – will be of greatest interest. Here Hesketh explains how genome sequencing has begun to change how cancers are diagnosed and classified, and the promise this holds for therapy. We are at the beginning, he writes, of the era of personalized medicine, which holds the promise that we will someday be able to detect the threat of cancer long before it manifests itself by sequencing an individual’s genome and using that information to design an individualized therapeutic strategy. The back matter includes a helpful glossary and two delightful odes to cancer, one written in 1964 by the noted geneticist (and cancer patient) J.B.S. Haldane and the other a modern version by Hesketh.

Despite the author’s occasionally breezy style – “cancer is jolly complicated” – this is not a book to breeze through, but rather a solid account of how cancer works, how it has been combated and what the future holds for its treatment.

https://www.kirkusreviews.com/search/?q=hesketh&x=16&y=13

3.  Nature 485, 579 (31 May 2012): It afflicts one in three people globally and kills more than 7 million a year. Yet cancer is, at base, simply an abnormal growth of cells. In this admirably clear overview, biochemist Robin Hesketh gives us the history, basic science and characteristics of cancer cells, charting how tumours spread and detailing genetics, detection, therapies and drugs. There is much to fascinate — from eighteenth-century physician Percivall Pott’s deduction that there was a link between soot and scrotal cancer in chimney sweeps, to the challenges of treating the biological “hodgepodge” that is a tumour.

http://libsta28.lib.cam.ac.uk:2157/nature/journal/v485/n7400/full/485579a.html

4.  John P. Moore, Professor of Microbiology and Immunology, Weill Cornell: In Betrayed by Nature, Robin Hesketh melds medicine, science and history to create a clear and highly readable explanation of the complexities of cancer.

5.  Interview on The Leonard Lopate Show: lopate050812apod.mp3

6.  For Amazon reviews see their web site.