No It Isn’t!

 

It’s great that newspapers carry the number of science items they do but, as regular readers will know, there’s nothing like the typical cancer headline to get me squawking ‘No it isn’t!” Step forward The Independent with the latest: “Major breakthrough in cancer care … groundbreaking international collaboration …”

Let’s be clear: the subject usually is interesting. In this case it certainly is and it deserves better headlines.

So what has happened?

A big flurry of research papers has just emerged from a joint project of the National Cancer Institute and the National Human Genome Research Institute to make something called The Cancer Genome Atlas (TCGA). This massive initiative is, of course, an offspring of the Human Genome Project, the first full sequencing of the 3,000 million base-pairs of human DNA, completed in 2003. The intervening 15 years have seen a technical revolution, perhaps unparalled in the history of science, such that now genomes can be sequenced in an hour or two for a few hundred dollars. TCGA began in 2006 with the aim of providing a genetic data-base for three cancer types: lung, ovarian, and glioblastoma. Such was its success that it soon expanded to a vast, comprehensive dataset of more than 11,000 cases across 33 tumor types, describing the variety of molecular changes that drive the cancers. The upshot is now being called the Pan-Cancer Atlas — PanCan Atlas, for short.

What do we need to know?

Fortunately not much of the humungous amounts of detail but the scheme below gives an inkling of the scale of this wonderful endeavour — it’s from a short, very readable summary by Carolyn Hutter and Jean Claude Zenklusen.

TCGA by numbers. The scale of the effort and output from The Cancer Genome Atlas. From Hutter and Zenklusen, 2018.

The first point is obvious: sequencing 11,000 paired tumour and normal tissue samples produced mind-boggling masses of data. 2.5 petabytes, in fact. If you have to think twice about your gigas and teras, 1 PB = 1,000,000,000,000,000 B, i.e. 1015 B or 1000 terabytes. A PB is sometimes called, apparently, a quadrillion — and, as the scheme helpfully notes, you’d need over 200,000 DVDs to store it.

The 33 different tumour types included all the common cancers (breast, bowel, lung, prostate, etc.) and 10 rare types.

The figure of seven data types refers to the variety of information accumulated in these studies (e.g., mutations that affect genes, epigenetic changes (DNA methylation), RNA and protein expression, duplication or deletion of stretches of DNA (copy number variation), etc.

After which it’s worth pausing for a moment to contemplate the effort and organization involved in collecting 11,000 paired samples, sequencing them and analyzing the output. It’s true that sequencing itself is now fairly routine, but that’s still an awful lot of experiments. But think for even longer about what’s gone into making some kind of sense of the monstrous amount of data generated.

And it’s important because?

The findings confirm a trend that has begun to emerge over the last few years, namely that the classification of cancers is being redefined. Traditionally they have been grouped on the basis of the tissue of origin (breast, bowel, etc.) but this will gradually be replaced by genetic grouping, reflecting the fact that seemingly unrelated cancers can be driven by common pathways.

The most encouraging thing to come out of the genetic changes driving these tumours is that for about half of them potential treatments are already available. That’s quite a surprise but it doesn’t mean that hitting those targets will actually work as anti-cancer strategies. Nevertheless, it’s a cheering point that the output of this phenomenal project may, as one of the papers noted, serve as a launching pad for real benefit in the not too distant future.

What should science journalists do to stop upsetting me?

Read the papers they comment on rather than simply relying on press releases, never use the words ‘breakthrough’ or ‘groundbreaking’ and grasp the point that science proceeds in very small steps, not always forward, governed by available methods. This work is quite staggering for it is on a scale that is close to unimaginable and, in the end, it will lead to treatments that will affect the lives of almost everyone — but it is just another example of science doing what science does.

References

Hutter, C. and Zenklusen, J.C. (2018). The Cancer Genome Atlas: Creating Lasting Value beyond Its Data. Cell 173, 283–285.

Hoadley, K.A. et al. (2018). Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer. Cell 173, 291–304.

Hoadley, K.A. et al. (2014). Multiplatform Analysis of 12 Cancer Types Reveals Molecular Classification within and across Tissues of Origin. Cell 158, 929–944.

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Put A Cap On It

If you’re not too selective in your reading you may have spotted ‘a new test which can predict with 100 per cent accuracy whether a person will develop cancer up to 13 years in the future’ trumpeted, needless to say, by The Telegraph and The Independent. No one with much of a clue about biology would write such a line and, somewhat surprisingly, it was left to the Daily Mail to produce a more balanced account of a study from Northwestern University that measured the length of telomeres in blood over time to see if that could be used as a marker for cancer development.

How long is a cap?

Telomeres: protective DNA caps on the ends of chromosomes

Telomeres: protective DNA caps on the ends of chromosomes

Telomeres are short, repeated sequences of DNA that ‘cap’ the ends of our 46 chromosomes but the cell machinery that makes DNA can’t manage to replicate the tips of the caps, so every time a new cell is made the ends of each telomere get lost. Which is of no matter to individual cells (as telomeres don’t code for protein) but their continuing loss in all cells would mean the species couldn’t survive. Accordingly, germline cells (through which sexual reproduction occurs) make an enzyme called telomerase that can achieve the trick of replicating the ends of chromosomes. In all other types of cell, however, telomerase is almost undetectable—its gene is still present, of course, but its almost completely ‘switched off,’ never to be turned on again. Never, that is, unless the cell becomes a tumor cell – most primary tumours make substantial amounts of telomerase, so they can maintain the length of their telomeres and can grow indefinitely.

The new study showed, as expected, that the telomeres in white blood cells get shorter with age but the striking finding was that, on average, shortening happens a shade more rapidly in individuals who went on to develop cancer than in those who did not. However, for the cancer group in the three to four years before diagnosis telomere attrition ceased, cap length becoming relatively stable, presumably as a result of telomerase being switched on. In other words, it seems that cancer development may actually increase telomere shortening in the period before telomerase kicks in to maintain ‘immortality’ in the tumour cell. The presumption is that this effect shows up in white cells in circulating blood because at least some of them will have encountered the ‘tumour microenviroment’ that we visited last time.

And the truth of the matter …

Do these results justify the headlines that (yet again) so annoyed me? As ever, it’s not a bad idea to read what the boffins who did the work actually said about their study, to wit, that it “… enabled us to establish temporal associations between blood telomere length and cancer risk … However, our findings should be confirmed in future studies. Our sample size limited our ability to analyze specific cancer subtypes other than prostate cancer. Thus, caution should be exercised in interpreting our results as different cancer subtypes have different biological mechanisms, and our low sample size increases the possibility of our findings being due to random chance and/or our measures of association being artificially high.”

Well said lads: no hype there, just an honest assessment – but bear in mind if you ever tire of science you’ll never get a job as a journalist.

Reference

Hou, L. et al. (2015). Blood Telomere Length Attrition and Cancer Development in the Normative Aging. EBioMedicine doi:10.1016/j.ebiom.2015.04.008.

Gentlemen! For goodness’ sake …

I reckon there should be a 21st century addition to the family etiquette handbook banning laptops at the breakfast table. It’s anti-social and indeed downright rude: at best you get to your emails ten minutes quicker but it’s also really stupid because computers do not thrive on a diet of milkdrops, cornflake fragments and bits of toast. I never appear without mine – and with it I bring another potential, disgraceful side-effect, manifested in our household on the second day of the New Year when, a few minutes after I’d sat down, booted up and started munching, the air gradually began to turn blue. “Oh dear” muttered youngest son: “he’s on to the science pages of the broadsheets: fingers in ears.” How shrewd. And what good advice.

Rattling my cage

So what was it that so wound me up when I was looking forward to a rather non-sciency, tranquil opening to the year? “Most cancers are caused by bad luck not genes or lifestyle, say scientists”, a headline trumpeted by The Telegraph was a great start, backed-up by much the same parroted in The Independent and The Guardian. The only good news was that, try as I did, I could find no equivalent coverage in The New York Times or The Sydney Morning Herald. Let’s hear it for the colonials – or at least their science editors!

What’s my problem?

Why is it that this sort of journalism so annoys and certainly did so on further reading of those new year contributions? Well, partly because it’s headline-driven rather than a thoughtful effort to inform the public. And then because what’s propagated isn’t totally wrong – that would be easy to deal with – but rather it’s a confused mish-mash of half-truths guaranteed to confuse utterly anyone who doesn’t have an assured grip on their molecular wits.

Let’s get things clear

First let’s get the basic picture clear, then see what “the scientists” really said in this new piece of work and finally illustrate how the Gentlemen (and Gentlewomen) of the Press get me so incensed.

Asked to sketch a current cancer portrait one might say: Cancers are caused by damage to DNA, i.e. mutations. Of our 20,000 or so genes several hundred can acquire mutations that change the activity of the proteins they encode to contribute to cancer development. Only a small number (half a dozen or so) of these ‘driver’ mutations, acting together, are required for cancer to emerge. Thus almost limitless combinations of drivers can arise. The effect of these cancer ‘drivers’ is to make cells proliferate (i.e. divide to make more cells) either at a faster rate than normal, or at the wrong time or in an abnormal place. Environmental factors (e.g., smoking) can increase the mutation rate and hence the chance that cancers will evolve. Most mutations accumulate during the lifetime of the individual (hence most cancers are ‘diseases of old age’). However, about 10% of cancers are started by inherited mutations (that the patient is born with), with further mutations being acquired after birth.

We should also bear in mind that collectively cancer comprise about 200 distinct diseases and that at the level of DNA sequence every tumour is unique.

Pancreatic cancer cells

 

Cancer cells dividing. Photograph: Visuals Unlimited, Inc./Dr. Stanley Flegler.

 

 

 

What’s new?

The work that the journalists caught on to didn’t describe any new experiments but instead looked at the long-standing puzzle of why cancers, although able to arise anywhere in the body, have a strong tissue bias. For example, tumours are twenty times more common in the large intestine than in the small intestine.

Noting that within many tissues most cells are short-lived and don’t give rise to progeny (and so are unlikely to initiate a tumour), the authors focused on the cells that can self-renew and are therefore responsible for the continued existence and repopulation of the tissue (often called stem cells). Searching the literature, they found 31 tissue types for which it was possible to work out how many stem cell divisions occur in an average human lifetime. Lo and behold, it turned out that the number of divisions correlated quite well with the lifetime risk for cancer in that tissue type i.e. the more replications of stem cells that a tissue requires over its lifetime to sustain its functional, the greater the risk of a tumour emerging in that tissue.

An interpretation of this is that the majority of cancers arise (i.e. are started) as a result of random mutations occurring during DNA replication in normal, non-cancerous cells. The underlying point here is that every time one cell makes two it must first duplicate its genetic material (i.e. replicate its DNA). This process is amazingly efficient but it’s not perfect (cells make a mistake once for every one thousand million coding units (i.e. bases) incorporated into new DNA). In the abstract of their paper the authors describe cancers initiated by these naturally occurring mutations as “bad luck” – unfortunately in my view, as the expression was a sure-fire red rag to the press bulls.

A really irritating example

From The Telegraph: “For years health experts have warned that tumours are driven by a bad diet, lack of exercise, or gene errors passed down from parents… But now a study has shown that most cancers are primarily caused by bad luck rather than poor lifestyle choices or defective DNA.”

NO IT HASN’T. Do you not read what you’ve written and consider how it might come across to readers who think they’ve grasped the basic picture, as summarized above under Let’s get things clear?

What the study confirms is that the major force behind cancers is the accumulation of mutations (defective DNA if you wish) as cells replicate during the lifetime of the individual. To the risk of getting cancers posed by this background to life may be added environmental factors that promote DNA damage and inherited variants in DNA (see A Taxing Inheritance for more about parental contributions).

Is this really anything new?

Well, it’s marginal and certainly not enough to merit the above headlines. The new work doesn’t alter in any way our summary. However, it’s interesting in that it offers an explanation for the wide variation in cancer incidence across different tissues and makes the point, for instance, that the relatively high rate of cell renewal in the lung makes this organ particularly susceptible to the mutagenic effects of cigarette smoke.

So, what about luck?

First we remain as we were: cancers are a fact of life – they’re hard-wired into the biology of life and they’ll come to all of us if we live long enough.

It is certainly true that there are many cancer patients who have had bad luck. They may have always eaten healthily, kept active and physically fit and been teetotal since birth and yet be stricken by, for example, a brain tumour or pancreatic cancer for which there are no known environmental risk factors that we can do anything about. They may have never smoked but nonetheless develop lung cancer (think of Roy Castle).

But it remains the case that for many cancers, it isn’t just about luck, it’s about choices, both for society and for individuals. Mention of environmental factors reminds us that mankind really isn’t doing very well on the self-help front. Eliminating smoking would reduce the global cancer burden (14 million new cases, over 8 million deaths per year) by about 22%. Infections, for example from contaminated drinking water, start about 20% of all cancers whilst alcohol consumption has a hand in about 4% and in the UK over 20% of bowel cancers are linked to eating red and processed meat.

Calm down!

I know that for all the effect my wittering about the quality of science journalism will have I might as well get on to the sports pages. I actually have some sympathy with the Gentlemen of the Press: writing about science is difficult – perhaps we should rejoice that there’s any national coverage. But there is a recurrent problem in the British press (see Not another ‘Great Cancer Breakthrough’!!!) that can easily be avoided. Just report evolving science stories as precisely and clearly as possible. They’re often sensational tales in their own right, so leave the sensationalism to the other pages and tell it as it is.

Rant over. Happy new year. Now, where’s the marmalade?

References

Tomasetti, C. and Vogelstein, B. (2015). Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 347, 78-81.

Delay Olympics for eight years, says biochemist

No he didn’t because that would just be silly wouldn’t it? What my colleague Chris Cooper from the University of Essex was reported as saying by The Independent was “Delay awarding London 2012 Olympic medals for eight years” because he thinks it will take that long for drug tests to separate who was playing the game (cricket, obviously) from the cheats – the word taken from Chris’s book Run Swim, Throw, Cheat.

The current front-runner in the game of Beat the Biochemists appears to be erythropoietin (EPO) – a natural hormone that makes us produce more red blood cells. That’s handy if you go in for endurance events (like surviving t.v. coverage of the Olympics). The Boffins went 1 – 0 up recently by coming up with a test that picks up EPO after it’s been injected.

You don’t know how lucky you are!

In the second leg the Scoundrels have hit back with fiendish cunning. A key factor that regulates whether we make EPO is oxygen availability. Lower oxygen means more red cells needed. But for that to happen there has to be a molecular messenger that can sense oxygen levels. There is: it’s a protein called hypoxia-inducible factor (HIF, of course) that under normal conditions gets broken down very quickly – by a process that needs oxygen. So when oxygen drops HIF lasts longer, makes more EPO and that makes more red cells. The crafty bit is finding another molecule that stabilizes HIF – in effect, enables it to survive even when there’s plenty of oxygen. HIF stabilizers are potentially important in treating some diseases and they’re just the ticket if you want to cheat in the 5,000 km bog snorkel.

There’s a bit of a concern because HIFs play an important role in helping cancers to grow so, adding that to the stress of wondering if you’re going to be nicked, it’s all going to be a bit of a strain for any ‘athletes’ who succumb to temptation. But there’s a time-honoured way of dealing with stress and this isn’t the moment to spoil the ship. A pack a day should do the trick.

Sorted. It’s all systems go for gold in the true Olympian spirit, Lucky Strikes in one pocket, HIF stabilizers in the other, morals in the changing room. The Boffins are scuppered, at least until they can find a way of detecting the invisible EPO driver, unless of course the fags give things away. What the score-line will be when we hear the merciful blast of the final whistle on 12th August is anyone’s guess – but for once I wouldn’t bet on the Boffins.

So who was the idiot responsible for the title of this piece? What could have possessed him? I have no idea but here’s a guess. What if he thought: let’s ban the Olympics for two rounds – and come 2020 everyone will say “Gee, what a great eight years we’ve had with none of the colossal waste of money on these staggeringly over-hyped, extraordinarily tedious and somewhat malodorous events. Let’s not bother any more.” Give that man a medal – without delay!

Reference

http://www.independent.co.uk/sport/olympics/news/delay-awarding-london-2012-olympic-medals-for-eight-years-says-biochemist-7917937.html

Not another ‘Great Cancer Breakthrough’!!!

Since I started writing Betrayed by Nature and this accompanying blog, my take on science reporting in the ‘media’ has undergone considerable change. I guess most of it used to wash over me: now I feel obliged to read it, with a view to making sense of it from the point of view of non-scientists. The dramatic headlines generally fall into two groups – one telling us what not to do/eat, the other revealing how wonderful scientists are.

I admitted recently (Whose side are you on?) that as far as the eating, drinking and exercising injunctions go, I’m beginning to side with those who just wish ‘they’d’ keep quite and let us get on doing whatever we want to do. The other group is trickier because there’s almost always some interesting stuff beneath the press rhetoric. The latest Scientists hail revolutionary breast cancer breakthrough is a case in point. The media coverage refers to a paper just published in Nature that has applied the formidable power of nucleic acid sequencing methods to a large number of breast tumours. The sheer amount of information generated is almost stupefying and the efforts of folk – called ‘bioinformaticists’ – who make sense of the raw data are remarkable.

But the overall message is relatively simple. Like every other tumour, each breast cancer is different at the level of the molecular changes it carries. However, the DNA sequences of genes and the extent to which they are ‘switched on’ to make RNA and protein (‘gene expression’) permit these tumours to be sub-divided into 10 major categories.

So is this a ‘Great Cancer Breakthrough’. Not really. It’s a terrific piece of science but it’s just one more small step towards better designed therapies that’s come from using the wonderful methods that have become available over the last ten years or so.

Did the guys who did the work use the hyped-up language of Mr. Connor in The Independent? Not exactly. This paper is a stunning technical tour-de-force – but the authors merely sign off with the comment that their work ‘reveals novel subgroups that should be the target of future investigation’.

Reference

Curtis, C., Shah, S.P., Chin, S.-F., Turashvili, G., Rueda, O.M. et al. (2012). The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature (2012) doi:10.1038/nature10983