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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Biting the bitter bullet

The other day we took a short trip around obesity (Obesity and Cancer) in the course of which we noted that the former is a bad thing. So, you might say, they make a good pair – indeed they quite often come hand-in-hand, as obesity significantly increases the risk of quite a lot of cancers as well as other unpleasant conditions. The nasty effects include heart diseases and diabetes, a collection of problems often referred to as metabolic syndrome.

Fed up?

Obesity is usually caused by eating too much of the wrong stuff whilst parked on your rear end. True enough, but folk sometimes get a bit cheesed off by repeatedly being told to do something about it. As it happens, turning to Cheddar, if you can face the stuff, may actually help weight loss as cheese is high in protein and fills you up. And you might just go for that escape route when you’ve been leaned on by a recent article that, in effect, calls for draconian measures to limit the amount of sugar we eat. To be slightly more precise, the target is the USA because, as is well known, Americans lead the world in pretty well everything, including bad eating habits. The scientific dynamite propelling the charge is that sugar consumption worldwide has gone up three-fold in the last 50 years. The average American now eats over 600 grams of the stuff every day, a feat that leaves the rest of the world scarcely within range of a podium spot. It may seem a bit odd to be left trailing at anything by the most obese nation in the world (let’s leave Nauru –pop. 9265 – and a few other South Sea islands out of it)  but the link here is, of course, that sugar is a great source of calories and that the more calories you shovel down – in whatever form – the bigger you tend to become. But don’t get too cheeky about Yankee obesity as us Brits aren’t in great shape either.

Condensed facts

Very roughly an ‘average’ person needs about 2,100 calories a day. 600 grams of sugar would give between one third and one quarter of that total requirement. For an historical perspective that’s about 14 times as much sugar as the denizens of Great Britain were allowed during the second world war under rationing – a period when our diet is generally considered to have made us healthier than we’ve ever been. So you could say an element of control has been lost.

Calorific confusion

The ‘2,100 calories’ above are ‘food calories’, the unit sometimes used in nutritional contexts. It’s 1000 times bigger than ‘scientific’ calories, or gram calories (cal). Scientifically therefore, we mean 2,100 kilocalories (kcal). Which is why your fruit juice carton may tell you one glass contains 50 kcal. And, just to stop you asking, 1 calorie is the heat (energy) you need to raise the temperature of 1 gram of water from 14.5oC to 15.5oC.

An all-round view of the problem

Sugar consumption has ski-rocketed, eating too much of it unbalances your diet and bad eating habits can cause obesity and metabolic syndrome. But these things aren’t black and white: 20% of obese people have normal metabolism and a normal lifespan whilst 40% of those of normal weight will get metabolic syndrome diseases. So, whilst obesity indicates metabolic abnormality, it is not per se the cause.

The underlying science remains a matter of debate – a story well summarized by Gary Taubes. What is not in question is that we eat more sugar than we need and the real crunch is that sugar is like tobacco and alcohol – no, it doesn’t make you smelly or do Sinatra impressions – but it is addictive. It actually manipulates your pathetic brain cells so you keep asking for more.

On your Marx

So we’re seduced into eating more and more of something that can help us get fat and ill. What’s to be done? Lenin, who was fond of asking this question, would have dealt with it in a trice by limiting sugar supplies to one tenth of the dietary minimum and seeing who survived. Ah! The good old days. But the authors of the recent article had to come up with a pc 21st century equivalent. Of course! Taxation. And they’ve a point – you can tell people that smoking will give them lung cancer til you’re blue in the face but the only thing that stops them committing suicide is jacking the price up. Don’t ask me. Something to do with human nature. So it sounds like a good idea – but to have an effect on sugar you’d need a huge increase across a vast range of foods – fruit juice, ‘sports’ drinks, chocolates, sweets, cakes – forget it.

Do I have a solution? Of course! Bring back rationing. For all foods. Set at the UK second world war levels. Now we’d think about what we eat – carbohydrate, protein and fat – reverse obesity trends, solve world food problem, slash health service costs, cut queues at supermarkets (so they’d be normarkets). And we’d be rid of most of those damned cheffy t.v. programmes. Vote for me!!

Reference

Lustig, R.H., Schmidt, L.A. and Brindis, C.D. (2012). The toxic truth about sugar. Nature 482, 27-29.

Gary Taubes (2011). Is Sugar Toxic? The New York Times.