Wonder of the World

Welcome back from our holidays on which, we trust, you had as much fun reading the four refresher pieces as I had writing them. Utter nonsense, of course. I’ve never found writing to be an orgasmic activity but, as they say about cod liver oil, it is good for you. However, whilst we were all improving ourselves on our deck-chairs and sun-loungers, the Tide of Science was waiting for no man: the waves of cancer biology have obliterated our sand castles and are fast approaching our toes. So let’s get on – albeit doing our best to make the segue from vacation to vocation as seamless as possible …..

So, on the subject of holidays, newspapers and magazines rather like the theme of ‘places to visit before you die’ – which is OK in that the world is wonderful and we should appreciate it. But there’s a problem in that one of the modern wonders is being able to see magnificent photos and movies of every far-flung nook, cranny and creature without leaving our sofa. So when we finally do get off our rear ends and chug past the Statue of Liberty on the Staten Island Ferry, zoom into Sydney or rock up to the Taj Mahal, the reaction is likely to be ‘That’s nice: looks just like on tv. Where next?’

Fortunately, being blasé has its limits. The only time I’ve made it to the Grand Canyon the mid-winter sun highlighted the colours of the rock striations so they were breathtaking in a way no photograph could quite capture. In the same vein, everyone should take the Trans-Siberian Railway we’re often told. And so you should but not because you will see houses and churches, rivers and trees that you can’t find on the Internet but because only borne by the train do you begin to sense the immensity of Mother Russia. The fact that the scenery is almost entirely birch trees minimizes distraction: all you can do is contemplate vastness – and the harshness that brings – an unvarying obbligato to Russian life.

A Provodnitsa looking after one of her passengers on The Trans-Siberian Railway

A Provodnitsa looking after one of her passengers on The Trans-Siberian Railway

The thrice-weekly freight at Grand Canyon Station, circa 1970

The thrice-weekly freight at Grand Canyon Station, circa 1970

 

 

 

 

 

 

Not Forgetting

All of which brings us to something else that is also truly a wonder of the world – cancer. If it seems a trifle weird to describe thus what’s usually classed as one of man’s greatest blights, consider this. The drive to control cancer has generated research on a scale unmatched in any other field of science. One upshot, not necessarily at the top of the list, is that we now have a breathtakingly detailed picture of the astonishing adaptability of life  – that is of our genetic material, DNA, and how its calisthenics can promote the most incredible behaviour on the part of individual cells. It’s true, you might point out, that we can see this by simply looking at the living world around us. The power of DNA to carry, in effect, limitless information produces the infinite cellular variety underpinning the staggering range of life that has evolved on earth. {Did you spot just the other day that a school field trip discovered 13 new species of spider in Queensland – yes, thirteen – inevitably headlined by The Sun as Creepy Hauly}

In the new world

But in focusing on cancers – what happens at the molecular level as they develop and how they evade our attempts to control them – the fine detail of this nigh-on incomprehensible power has been revealed as in no other way.

You’ll know what’s coming: the biggest single boost to this unveiling has been the arrival in the twenty-first century of methods for sequencing DNA and identifying which genes are expressed in cells at any given time. I know: in umpteen blogs I’ve gone on about its awe-inspiring power – but it is stunning and we’re at that stage when new developments leave one gasping almost on a monthly basis. The point here is that it’s not that the science keeps getting turned on its head. Far from it: the message remains that cells pick up changes to their DNA and, with time, these cumulative effects may drive them to make more of themselves than they should.

That’s cancer. But what is fantastic is the molecular detail that the ’omics revolution continues to lay bare. And that’s important because, as we have come to recognize that every cancer is unique, ideally we need to provide specifically tailored treatments, and we can only think of doing that when we know all the facts – even if taking them in demands a good deal of lying down in darkened rooms!

You could think of the fine molecular detail of cancers as corresponding to musical ornaments – flourishes that don’t change the overall tune but without which the piece would be unrecognizable. These include trills and turns – and all musicians will know their appoggiaturas from their acciaccaturas. They’re tiny embellishments – but just try removing them from almost any piece of music.

Lapping at your toes

So let’s look at three recent papers that have used these fabulous methods to unveil as never before the life history of cancers. The first is another masterful offering from The Sanger Institute on breast cancer: an in-depth analysis of 12 patients in which each tumor was sampled from 8 different locations. In the main the mutation patterns differed between regions of the same tumour. They extended this by looking at samples from four patients with multi-focal disease (‘foci’ being small clumps of tumour cells). As expected, individual foci turned out to be clearly genetically related to their neighbours but they also had many ‘private mutations’ – a term usually meaning a mutation found only in a single family or a small population. Here the ‘family’ are individual foci that must have arisen from a common ancestor, and you could think of them as a cellular diaspora – a localised spreading – which makes them a kind of metastasis. Quite often the mutations acquired in these focal sub-clones included major ‘driver’ genes (e.g., P53, PIK3CA and BRCA2). In general such potent mutations tend to be early events but in these foci they’ve appeared relatively late in tumour development. This doesn’t upend our basic picture: it’s just another example of ‘anything goes’ in cancer – but it does make the point that identifying therapeutic targets requires high-depth sequencing to track how individual cancers have evolved through continual acquisition of new mutations and the expansion of individual clones.

The authors used ‘coxcomb’ plots to portray these goings-on but they are quite tricky to make head or tail of. So, to avoid detail overload, I’ve converted some into genetic wallpaper, the non-repeating patterns illustrating the breathtaking variety that has evolved.

Wallpaper jpegDecorative DNA. The discs are ‘coxcomb’ plots – a variant of a pie chart. Here the colours and the wedge sizes represent mutations in different regions of four primary breast tumours. Every disc is different so that the message from this genetic wallpaper is of mutational variation not only between cancers but across the different samples taken from a single tumour. I trust that Lucy Yates, Peter Campbell and their colleagues will not be too upset at my turning their work into art (and greatly abbreviating the story): you can read the original in all its wondrous glory in Nature Medicine 21, 751–759.

The first person to come up with this very graphic way of conveying information was Florence Nightingale who, whilst working in Turkey during the Crimean War, realized that soldiers were dying in the hospitals not only from their wounds but, in much greater numbers, from preventable causes including infections, malnutrition and poor sanitation. Her meticulous recording and original presentation of hospital death tolls made her a pioneer in applied statistics and established the importance of sanitation in hospitals.

Something for the gentlemen

Two equally powerful onslaughts from Gunes Gundem, Peter Campbell and their colleagues at The Sanger Institute (again!) and Dan Robinson and pals from the University of Michigan Medical School have revealed the corresponding molecular detail of prostate cancer. Here too the picture is of each region of a tumour being unique in DNA terms. Moreover, they showed that metastasis-to-metastasis spread was common, either through the seeding of single clones or by the transfer of multiple tumour clones between metastatic sites.

Even that miserable old sod Lenin might have brightened at such fabulous science, before reverting to Eeyore mode with the inevitable “What’s to be done?” But it’s a good question. For example, as a general strategy should we try to kill the bulk of the tumour cells or aim for clones that, although small, carry very potent mutations.

Aside from the basic science, there is one quite bright ray of sunshine: about 90% of the mutations linked with the spread of prostate cancer are potentially treatable with existing drugs. And that really is encouraging, given that the disease kills 11,000 in the UK and over 30,000 in the USA every year.

prostate dogWe might also be heartened by the skills of German Shepherd dogs that can, apparently, be persuaded to apply one of their favourite pastimes – sniffing – to the detection of prostate cancer. Point them at a urine sample and 90% of the time they come up with the right answer. Given the well-known unreliability of the prostate-specific antigen blood test for prostate cancer, it’s nice to think that man’s best friend is on the job.

References

Yates, L.R., et al. (2015). Subclonal diversification of primary breast cancer revealed by multiregion sequencing. Nature Medicine 21, 751–759.

Robinson, D., et al. (2015). Integrative Clinical Genomics of Advanced Prostate Cancer. Cell 161, 1215–1228.

Gundem, G., et al. (2015). The evolutionary history of lethal metastatic prostate cancer. ICGC Prostate UK Group (2015). Nature 520, 353–357.

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The Blink of an Eye

You might not have thought of it in quite this way but cancer biology is a bit like having kids. It seems you only have to turn your back and things have changed, not so as to be unrecognizable but enough to have you blinking in surprise, shock or horror. In the cancer field it’s true that, especially over the 12 years since human DNA was first completely sequenced, a fair bit of the jaw-dropping has been due to astonishing technical advances. Thus human genomes (i.e. their DNA sequence) can be laid bare in 24 hours – The International Cancer Genome Consortium now has over 10,000 cancer genomes in its database – and the power of the panoply of ’omics methods to probe ever deeper into the mind-boggling complexity of tumours is quite staggering (we risked a quick peep at just how tricky it is to disentangle a picture of the biology from the vast amounts of data in A Word From The Nerds).

Cancer’s simple

These revelations often leave us gasping at the variety and adaptability of nature and how that shows up time and again in the microworld of cancers. Of course, we’re used to the world being ever-changing but we like to think there are some things that are fixed. The Earth still rolled round the Sun even after the aeroplane was invented. When it comes to cancer the simple but fairly firm idea is that cells pick up changes in their genetic material (i.e. mutations in DNA) and if these affect an appropriate set of genes (i.e. encoded proteins) a cell starts misbehaving – multiplying when it shouldn’t or faster than normal. And that’s cancer. Of the twenty-odd thousand genes that make human beings, several hundred have this ability to be trouble-makers – and a handful at any one time (perhaps five to ten) is all it takes. Like any team, there are some high profile players: genes that crop up time and again in mutant form driving all sorts of different tumours. There’s maybe a dozen of these. The rest are bit part players: actors who can steal the show with a cameo role. In others words they’re low frequency cancer drivers, perfectly capable of doing the job but generally keeping a low profile.

All of which is fine: we can hang on to what we thought we knew. Cancers are caused by cumulative mutations – things are just complicated a bit because of the more or less infinite subtlety that the different combinations can cause. So cancer’s really pretty simple.

Oh no it’s not!

However, just once in a while – mercifully, or we’d all go potty – something comes along that has us, if not standing on our heads, at least wondering which way is up. Welcome Iñigo Martincorena, Peter Campbell and pals from The Sanger Institute in Cambridge – a regular source of wide-eyed wonder in genomics.

They’ve just done something that, on the face of it, was very odd. They carried out a thorough sequence analysis of samples of normal human skin, the skin in question being from eyelids. The plan was to try to get a picture of how cancers develop and eyelid skin is a good place to look because it gets a relatively high exposure to sun. Moreover, it’s easier to get hold of than you might think: there’s an age-related condition in which the skin loses its elasticity causing the eyelid to droop – which can be treated by surgery, i.e. cutting out some of the skin.

Fasten your seat belts: here comes the shaker. In 234 eyelid samples (biopsies) from four people the number of mutations was similar to that in many cancers! Yet more amazing, the mutated genes included most of the key ‘drivers’ of one of the major forms of skin cancer.

Putting numbers on it, they found about 140 driver mutations per square centimeter of skin.

The type of DNA damage was characteristic of the effect of ultraviolet light (e.g., changing C to T – i.e. the base cytosine is mutated to thymine) – so at least that wasn’t a surprise.

1 sq cm

Groups of mutant cells (clones) in a 1 square centimeter of normal eyelid skin.

The circles represent samples of skin that were sequenced. Their sizes and the representation of nested clones are based on the sequences obtained. The outermost layers of normal skin can therefore be viewed as “effectively a battlefield of hundreds of competing mutant clones in every square centimeter of skin.” (from Martincorena et al. 2015).

As Iñigo & Co put it ‘aged sun-exposed skin is a patchwork of thousands of evolving clones with over a quarter of cells carrying cancer-causing mutations.’ Notably, there were clones carrying two or three driver mutations – and yet the tissue showed no sign of cancer and functioned quite normally (apart from its wonky elastic).

Close your eyes: time for a re-think

So, there are thousands of mutations in each skin cell with hundreds of evolving clones per square centimeter and the profile of driver mutations varies between individuals. The obvious question, therefore, is ‘why isn’t this tissue cancerous?’ We don’t know but, given that key ‘drivers’ are present, it seems that these cells either have a kind of master ‘off switch’ that suppresses potent driver combinations or they need a further ‘on switch.’ There’s no evidence for either of these, nor is it clear whether other cell types can show this kind of restraint.

And there’s one more troubling point. Many cancer drugs are designed to target driver mutations and thus to kill the carrier cells. But if these mutations can crop up in normal cells, any such ‘cancer specific’ drugs might cause a good deal of what the military term collateral damage.

As ever in science, an exciting new finding raises yet more questions. Answers will be forthcoming at some point. Just don’t blink!

Reference

Martincorena, I. et al. (2015). High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880-886.