Dennis’s Pet Menace

As it happened, I’d already agreed to appear on Jeremy Sallis’ Lunchtime Live Show on BBC Radio Cambridgeshire – the plan being just to chat about cancery topics that might be of interest to listeners. Which would have been fine – if only The World Health Organization had left us in peace. But of course they chose last Tuesday to publish their lengthy cogitations on the subject of whether meat is bad for us – i.e. causes cancer.

Cue Press extremism: prime example The Times, quite predictably – they really aren’t great on biomedical science – who chucked kerosene on the barbie with the headline ‘Processed meats blamed for thousands of cancer deaths a year’.

But – to precise facts – and strictly it’s The International Agency for Research on Cancer, the cancer agency of the World Health Organization (WHO), that has ‘evaluated the carcinogenicity of the consumption of red meat and processed meat.’

But hang on … haven’t we been here before?

Indeed we have. As long ago as January 2012 in these pages we commented on the evidence that processed meat can cause pancreatic cancer and in May of the same year we reviewed the cogitations of the Harvard School of Public Health’s 28 year study of 120,000 people that concluded eating red meat contributes to cardiovascular disease, cancer and diabetes. To be fair, that history partially reflects why the WHO Working Group of 22 experts from 10 countries have taken so long to go public: they reviewed no fewer than 800 epidemiological studies! However, as the most frequent target for study was colorectal (bowel) cancer, that was the focus of their report released on 26th October 2015.

So what are we talking about?

Red meat, which means any unprocessed mammalian muscle meat, e.g., beef, veal, pork, lamb, mutton, horse or goat meat, that we usually cook before eating.

Processed meat: any meat not eaten fresh that has been salted, cured, smoked or whatever and commonly treated with chemicals to enhance flavour and colour and to prevent the growth of bacteria.

What did they say?

Processed meat is now classified as carcinogenic to humans – that is it goes into the top group (Group 1) of agents that cause cancer.

Red meat is probably carcinogenic to humans (Group 2A). Group 2B is for things that are possibly carcinogenic to humans.


Because 12 of the 18 studies they reviewed showed a link between consumption of processed meat and bowel cancer and because it’s known that agents commonly added to processed meat (nitrates and nitrites) can, when we eat them, turn into chemicals that can directly damage DNA, i.e. cause mutations and hence promote cancers.

For red meat 7 out of 15 studies showed positive associations of high versus low consumption with bowel cancer and there is strong mechanistic evidence for a carcinogenic effect i.e. when meat is cooked genotoxic (i.e. DNA-damaging) chemicals can be generated. They put red meat in the probably group because several of the studies that the Working Group couldn’t fault – and therefore couldn’t leave out – showed no association.

Stop woffling

My laptop likes to turn ‘woffling’ into ‘wolfing’. Maybe it’s trying to tell me something.

But is The WHO trying to tell us something specific about wolfing? To be fair, they have a go by estimating that every 50 gram portion of processed meat (say a couple of slices of bacon) eaten daily increases the risk of bowel cancer by about 18%. For red meat the data ‘suggest’ that the risk of bowel cancer could increase by 17% for every 100 gram portion eaten daily.

And what might that mean?

In the UK about 6 people in 100 get bowel cancer: if you take The WHO maximum estimate and have everyone eat 50 grams of processed meat every day of their lives such that 18% more of them would get bowel cancer, the upshot would be 7 people in 100 rather than 6. So it’s a small rise in a relatively small risk.

As the report points out, the Global Burden of Disease Project reckons diets high in processed meat cause about 34,000 cancer deaths per year worldwide and, if the reported associations hold up, the figure for red meat would be 50,000. Compare those figures with smoking that increases the risk of lung cancer by 20-fold and The WHO’s estimate of up to 6 million cancer deaths per year globally caused by tobacco use and 600,000 per year by alcohol consumption.

All of which suggests that it isn’t very helpful to lump meat eating, tobacco and asbestos in the same cancer-causing category and that The WHO could do worse than come up with a new classification system.

And the message?

Unchanged. Remember mankind evolved into the most successful species on the planet as a meat eater. As the advert used to say: It looks good, it tastes good and by golly it does you good – not least as a source of protein, vitamins and other nutrients. Do some exercise and eat a balanced diet – just in case you’ve forgotten, that means limit the amount of red meat (The WHO suggests no more than 30 grams a day for men, 25 g for women) so try fish, poultry, etc. Stick with the ‘good carbs’ (vegetables, fruits, whole grains, etc.), cut out the ‘bad’ (sugar – see Biting the Bitter Bullet), eat fishy fats not saturated fats and, to end on a technical note, don’t pig out.


‘The Divine Swine’ Castelnuovo Rangone, Italy

Meanwhile back on the Beeb

When the meat story broke I was a bit concerned that we might end up spending the whole of Lunchtime Live on how many bangers are lethal – especially as we were taking calls from listeners. Just in case things became a bit myopic I had Rasher up my sleeve. Rasher, you may recall, was Dennis the Menace‘s pet pig (in the The Beano‘s comic strip) who had a brother (Hamlet), a sister (Virginia Ham) and various other porky rellos. To bring it up to date we’d have introduced Sam Salami and Frank Furter and, of course, Rasher’s grandfather who was the model for the bronze statue named ‘The Divine Swine’ to be found in the little town of Castelnuovo Rangone in Pig Valley, Italy, the home of Parma ham.

But I shouldn’t have worried. All was well in the hands of Jeremy Sallis who, being a brilliant host, ensured that we mainly chatted about meatier matters than what to have for breakfast.


Press release: IARC Monographs evaluate consumption of red meat and processed meat.

Q&A on the carcinogenicity of the consumption of red meat and processed meat.

Carcinogenicity of consumption of red and processed meat. Published online October 26, 2015


Cancer Genetics: Never Black or White

The National Heath Service occupies a uniquely revered place in the psyche of the British people – as indeed it should, the concept of free, first rate health care available when required being one of the hallmarks of civilization. Founded in 1948, the NHS has continued to this day to fulfill its remit with astonishing efficiency in the face of demands beyond comprehension sixty years ago, as both the size of the population and life expectancy have increased and medical practice has been transformed by technical advances. Even so, there is one area in which there is a surprising shortfall in the performance of the NHS when compared with most other European countries or with the USA – cancer survival rates.

We’re behind you!!

Broadly speaking, the latest findings of a massive study (called CONCORD-2, a long-term global comparison of cancer survival) show 5-year cancer survival rates in the UK for 2005 to 2009 to have been worse than they were in many European countries at least a decade earlier. “Shameful” cried Macmillan Cancer Support – rarely a helpful response but you have to concede it’s scarcely grounds for an outbreak of British smugness. More to the point, Cancer Research UK insisted the gulf was often linked to deprivation, i.e. patients in poorer areas tend to live unhealthy lifestyles so they are more susceptible and likely to be diagnosed later. This refers to what has become known as the postcode (zipcode) lottery whereby the chances of being diagnosed early and surviving various forms of cancer differ significantly (meaning as much as two-fold!) across the UK. Further contributions come from general practitioners missing the early signs of cancer, adding to the delay in referral, together with variable standards of treatment.

And the answer is?

But hang on! None of this actually explains why these problems should be more acute in the UK than in, say, France or Finland who presumably have their share of the poor and incompetent. So what might be different in the UK? Here’s my theory. Maybe it’s just us, the Jane & John Does lining up to become cancer patients. Dentists reckon they can pick Brits from Yanks just by peering into their oral cavities (Brits have cavities {ho ho} whereas Americans are perfect – tooth-wise that is). Why? Because we don’t care: we figure our bodies are non-maintenance machines – so we never dream of getting them serviced, that is, having regular check-ups – and when they do conk out we expect the wondrous NHS to fix it. To see if there’s any truth in this theory I conducted a meaningless, random poll in my department (featuring two Americans, one Finn, a Dutchman, two German ladies and a French girl – all from nations that do better than the UK) asking ‘how health aware are your countrymen compared with the British?’ Result? They’re all hypochondriacs compared to Brits whose default method is to avoid doctors until they’re at death’s door. So there we have it: it’s our fault and if we just looked after ourselves a bit better the UK would scrabble its way up the cancer survival league.

Sounds familiar?

Take the specific example of breast cancer. 81% of UK women diagnosed between 2005 and 2009 were alive five years later but in Sweden, France and Italy the rates range from 86 to 87%. This kind of gap is reminiscent of that in the USA between African American women and those of European descent – presently 79% versus 92 % – a disparity that has remained pretty constant over the last 40 years even though the survival rates of both groups have steadily risen (the overall USA survival rate for breast cancer is now 89%). Again the divide has been attributed to poverty and education level, together with lack of health insurance, so that detection is delayed and survival times shortened.

So it’s clear that multiple factors contribute to the variable treatment success rates but so far there’s no evidence that genetic differences play a part, for example, by giving rise to more aggressive forms of cancer.

A little more light in one corner

Breast cancers are an enormously varied set of diseases and as such they’re a challenge even to classify yet alone to treat. The recent rapid progress in DNA sequencing has led to a new genome-based classification system but there is still strong reliance on the traditional prognostic and predictive factors, notably what’s called hormonal status – meaning presence on the surface of the tumour cells of the protein receptors to which the hormones oestrogen and progesterone attach, together with the presence or otherwise of the human epidermal growth factor receptor 2 (HER2). One significant sub-group has no detectable levels of these proteins – they’re ‘triple negative’ – and they make up 10-15% of breast cancers (TNBCs). TNBCs are very aggressive cancers (poor prognosis), known for some years to disproportionally affect young women of African origin – it’s about twice as common in African Americans as in European Americans.


The triple negative breast cancer survival rate dependence on race.

African-American women with TNBC have poorer survival rates than women of European descent (Dietze et al., 2015).

Step forward DNA sequencing – again!

What wasn’t known was anything by way of explanation of these epidemiological findings but from sequencing tumour DNA it has emerged that mutations in BRCA1 are present in most (69%) of TNBCs in women of European origin. Inherited mutations in BRCA1 are particularly associated with breast and ovarian cancers, as we explained in a recent item on Angelina Jolie (A Taxing Inheritance). But here’s a very odd thing: African-American women have a low incidence of BRCA1 mutations (less than 20%), despite the fact that they are relatively prone to TNBC.

What’s new?

Well, if BRCA1 isn’t doing the driving there must be other potent drivers for TNBC and the new genetic studies have given us one more piece in the molecular jigsaw of cancer. However, to take up Frances M. Visco’s point in a recent letter to The New York Times and one that I have made forcefully elsewhere (in Not another ‘Great Cancer Breakthrough’!!! and Gentlemen! For goodness’ sake …), this is not another ‘breakthrough’ yet alone a ‘great one.’ It won’t save lives until we identify what the other drivers are and come up with a therapeutic ploy to exploit our knowledge.

Right on cue, step forward Alex Swarbrick, Simon Junankar and colleagues from Sydney’s Garvan Institute of Medical Research who have just found that a protein called ID4 appears to control some TNBCs: it’s present at high levels in about half of all TNBCs. ID4 stands for ‘inhibitor of differentiation 4′ which means that it keeps cells in a state where they can continue to divide – a hallmark of cancer.

So now it’s over to the lads from down under to do the difficult bit and come up with an inhibitor of ID4 – and to show that it works to stop TNBCs in their tracks.


Allemani, C. et al., (2015). Global surveillance of cancer survival 1995-2009: analysis of individual data for 25 676 887 patients from 279 population-based registries in 67 countries (CONCORD-2). Lancet 385, 977-1010.

Dietze, E. et al., (2015). Triple-negative breast cancer in African-American women: disparities versus biology. Nature Reviews Cancer 15, 248–254.

Junankar, S. et al., (2015). ID4 controls mammary stem cells and marks breast cancers with a stem cell-like phenotype. Nature Communications 6, Article number: 6548 doi:10.1038/ncomms7548.


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?


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.

A Taxing Inheritance

The centenary of the beginning of the First World War prompted me, as perhaps many others, to reflect on how successive generations have done since then in terms of what they’ve bequeathed to their offspring. I didn’t need to think for too long though, to find myself muttering ‘Thank heavens for science’—because most of the rest is a pretty dismal chronicle. I know, not all technological advances in the past one hundred years have been a cause of unrestrained joy but many of them transformed life in the most wonderful ways. Would that we could point to such success in other fields.

Our best defence may be to aver: “Man cannot control the current of events. He can only float with them and steer”, a saying attributed to Otto von Bismarck. If the ‘Iron Chancellor’ actually did utter those words it seems to me he was being coy beyond belief. He is, after all, generally credited with unifying Germany, seeing off the last French monarch (Napoleon III) and establishing the peaceful domination of Europe by the German Empire that lasted until long after his death—and setting up the first welfare state along the way. “The main thing is to make history, not to write it” sounds much more like Bismarck in full and frank mode.

Nature and Nurture

One form of history that we do write but indeed we cannot control comes in the form of the genetic material that we pass to the next generation. We’re all familiar with some of this legacy because we literally see it in physical resemblances and other attributes between parents and children (“He’s got his Mum’s eyes”) or shared by siblings (“Jack and Jill are wonderful musicians”). They’re shared because large chunks of the genetic code (i.e. DNA) are identical between the individuals concerned. But if conserved DNA makes for similarities, what of the differences—the fact that our parents and brothers look different to all the seven thousand million other people on the planet? Our unique features come from variations in the genetic code—odd changes in the units (bases) of DNA scattered through our genome. Called SNPs (pronounced ‘snips’ for single nucleotide polymorphisms), they’re what make the differences between us. In other words, a SNP is a difference in a single nucleotide—A, T, C or G—within a stretch of DNA sequence that is otherwise identical between two individuals. For example, you have AAGCCTA whereas I have AAGCTTA. These genetic variations that make individuals different are the basis of DNA fingerprinting.

There’s about three million SNPs scattered throughout the human genome (so, on average, you’d come across one in every 1,000 bases if you scanned your DNA from beginning to end) and they’re what makes each of us unique. Within ethnic groups common patterns of such variants confer characteristics (dark skin/light skin, tall/short, etc) and, with that in mind, you might guess that there will also be variants that make such groups more (or less) susceptible to diseases.

Of course, there’s an endless debate about the border between our genetic inheritance and how the world we experience makes us what we are—how much of Jack and Jill’s precocious talent is because Mum and Dad made them practice twelve hours a day from age five? Fortunately we can ignore nurture here and stick to genes because we’re trying to pin down the good and the bad of our genetic legacy.

What’s all this got to do with cancer?

A good bit is that we’re distinct from everyone else but still share family features. However, our genetic baggage may also contain some unwanted freebies—the most potent of which can give a helping hand to a variety of diseases, including cancers. Cancers are caused by damage to DNA—a build-up of changes, i.e. mutations, that affect the activity of proteins critically involved in controlling cell growth. For most cancers (90%) these mutations accumulate over the lifetime of the individual—they’re called “somatic mutations”—so you can’t blame anyone but yourself and Lady Luck. But about 10% get a kind of head start when someone is born with a key mutation. That is, the mutated gene came from either egg or sperm (so it’s a germline mutation). This effect gives rise to cancers that “run in families”: a critical mutation is passed from generation to generation so that children who inherit it have a greatly increased risk of developing cancer. Two of the most common cancers that can come in hereditary form are those of the breast and bowel.


A mutational steeplechase leads to cancer. Of the tens of thousands of mutations that accumulate over time in a cancer cell, a small number of distinct “drivers” make the cancer develop (four are shown as Xs). Almost all mutations arise after birth, but about one in every ten cancers start because a person is unfortunate enough to be born with a mutation: they are already one jump ahead and are much more likely to get cancer than those born with a normal set of genes. The rate at which mutations arise is increased by exposure to carcinogens, e.g., in tobacco smoke.

Breast cancer is about twice as common in first-degree relatives of women with the disease as it is in the general population (you’re a first degree relative if you’re someone’s parent, offspring, or sibling). About 5% of all female breast cancers (men get the disease too but very rarely—about 1% of all breast cancers) arise from inherited mutations. In the 1990s two genes were identified that can carry such mutations. These are BRCA1 and BRCA2 and their abnormal versions can increase the lifetime risk of the disease to over 50%, compared with an average of about 10%. Since then heritable mutations in some other genes have also been shown to increase the risk.

Angelina Jolie

Angelina Jolie

A star turn

Breast cancer genetics came under the spotlight with the much-publicised saga of Angelina Jolie, the American film actress. Jolie’s mother and maternal grandmother had died of ovarian cancer and her maternal aunt from breast cancer—a family history that persuaded Jolie to opt for genetic testing that indeed revealed she was carrying a mutation in BRCA1 (BRCA1 and BRCA2 mutations account for about 10% of breast cancers and 15% of ovarian cancers). For Jolie the associated lifetime risk of breast cancer was estimated as 87%, prompting her to have a preventative double mastectomy, thereby reducing her risk to less than 5%. The months after she revealed her story saw the “Angelina effect”, a doubling in the number of women being referred for genetic testing for breast cancer mutations.

What’s all this got to do with SNPs?

The story so far is of the one in ten cancers that get kicked off by a powerful, inherited mutation that changes the action of the affected protein—the BRCAs being the best-known examples. However, the BRCAs and other known mutated genes account for only about 25% of familial breast cancers, meaning that for three quarters of cases the genetic cause remains unknown. And yet we know there is an inherited (genetic) cause simply because of the generational thread. Which brings us back to those other, more subtle tweaks to DNA that we mentioned—SNPs—alterations that don’t directly affect proteins, so they’re often called variants to distinguish them from mutations.

It seems very likely that the missing culprits are indeed SNPs—lots of them. These DNA variants each make a contribution so small that on its own would have no detectable effect on the chances that the carrier will get cancer. Their impact comes from a cumulative effect. They’re like pieces of straw, individually easily bent or broken but put a dozen of them together and you have a rope. Thus combinations of individually insignificant SNPs can raise the risk of cancer by, say, 10%—not a massive increase but not negligible either. Twins who are genetically identical have similar risks of developing breast cancer, consistent with the idea that many variants, each having a very small effect, can combine to give a substantial increase in risk. Very slowly, by sequencing lots of genomes, these rare variants are being identified. Given that clusters of appropriate variants confer risk, people with the “other” variant have, in effect, a degree of protection against cancer.

And in our more distant relatives?

All this comes from the huge effort that has gone into finding genetic variants linked to one of the most common cancers but, unsurprisingly, almost all the attention has focused on European women. Not before time, someone has got round to looking for breast cancer variants in East Asians who, after all, make up over one fifth of all the people in the world. Cai Qiuyin and his colleagues at the Vanderbilt University School of Medicine compared the genomes of over 20,000 cancer cases from China, Japan and South Korea with a similar number of disease-free controls. After much selecting and comparing of sequences, three particular DNA variants consistently associated with significant cancer risk. The variants were much less common in European women, suggesting that as the DNA keyboard has been strummed by evolution, distinct patterns associated with breast cancer have emerged in diverse populations.

Just two problems then. First it’s a huge task to assemble the lists of runners (and as the Asian results show, they will differ between ethnic groups). But the real challenge is yet to come. Almost all of these variants (99.9%) don’t change the sequence of proteins (i.e. how the proteins work). What they do is exert subtle effects on, for example, how much RNA or protein is made from a DNA gene at any time. At the moment we have little understanding of how this works, yet alone ideas on how to intervene to change the outcome.

Although identifying the BRCA genes that help to drive breast and ovarian cancers was a giant breakthrough, we still have no effective therapy for countering their malign influences. The intervening twenty-five years of effort have brought us to a new era of revealing the more subtle effects of variants. But the price we pay for unveiling the complete picture is perceiving just how tough is the therapeutic challenge.


Qiuyin Cai, et al. (2014). Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1. Nature Genetics 46, 886–890. doi:10.1038/ng.3041.

Risk Assessment

For UK readers a title that instantly raises the spectre of the ’Elf & Safety police and the annoyance, irritation and amusement generated by the seemingly ubiquitous injunctions of their minions. Even my department is not spared, the harbinger of warm weather invariably being an email reminding us that this is no reason for abandoning the rule that at all times we should wear a lab coat – though, to be fair, our local enforcer usually includes the cheeky inference that we retain the option of going naked underneath. Ah, The Joy of Science! ’E & S’s reputation comes, of course, from periodically making the headlines by banning a centuries-old tradition in some rustic backwater involving such fun activities as rolling cheeses down a hill.

Stuart Kettell and sprout

Stuart Kettell and sprout

Mind you, they’ve slipped up recently by allowing Stuart Kettell to push a Brussels sprout up Mount Snowdon with his nose. As that’s 3,560ft (vertically) he probably did lasting damage to his knees, to say nothing of his hooter, as well as inflicting grievous bodily harm on 22 sprouts (they wear out on the basalt, obviously). By his own admission, he’s probably mad – but he did at least raise some money for Macmillan Cancer Support.


But why are we bothered about assessing risk?

Setting the above entertainment to one side, estimating risk can be a really serious business and never more so than when it comes to cancer. It’s an especially contentious, long-running issue for breast cancer and both in Betrayed by Nature and more recently in Behind the Screen I tried to crystallize some clear guidelines from the vast amount of available info. In short these were: ignore commercial plugs for thermography – the only test to go for is mammography – i.e. X-ray imaging to find breast cancer before a lump can be felt. And the simple message you were relieved to read in BbN was that, whilst the matter is controversial, if you are offered screening, accept – but be aware that the method is not perfect. There’s a small risk that a cancer may be missed and a bigger chance that something abnormal but harmless will be picked up – a signal for intervention (by surgery and drugs) and that, in those cases, would be unnecessary.

And we’re revisiting this question?

Because there have been some recent contributions to the debate that might well have increased confusion and concern in equal measure for women who are desperately trying to make sense of it all. The most controversial of these comes from a panel of experts (The Swiss Medical Board) who reviewed the history of mammography screening – and recommended that the current programmes in Switzerland should be phased out and not replaced.

Needless to say, their report caused a furore, not only in Switzerland, with experts damning its conclusions as ‘unethical’ – mainly because they ran counter to the consensus that screening has to be a good thing.

So what did the Swiss Big Cheeses point out to get into such hot water? Their view after considering the cumulative evidence was that systematic mammography might prevent about one breast cancer death for every 1,000 women screened. However, two other things struck them. First, it was not clear that this result outweighed the disadvantages of screening – what are inelegantly referred to as the ‘harms’ – the detection and treatment of something ‘abnormal but harmless’ mentioned earlier. Second that, on the basis of a survey by American group, women had a grossly optimistic idea of the benefits of mammography.

Good versus bad

Two of the weightiest bits of evidence that led them to conclude that screening does more harm than good were studies that had combined several independent investigations – what’s called a meta-analysis – which is a way of increasing your sample size and hence getting a more meaningful answer. One of these (The Independent United Kingdom Panel on Breast Cancer Screening) pulled together 11 trials from which it emerged that women invited to screening had a reduction of about 20% in their risk of dying from breast cancer compared with controls who were not offered screening. So far so good. However, inevitably there were differences in methods between the trials, which made the UK Panel very cagey about drawing more specific conclusions but their best estimate was that, for every 10,000 UK women aged 50 years invited to screening for the next 20 years, 43 deaths from breast cancer would be prevented and 129 cases would be over-diagnosed. Over-diagnosis means detection of cancers that would never have been emerged during the lifetime of the individuals and these healthy women will be needlessly subjected to some combination of surgical interventions, radiotherapy and chemotherapy.

The second combined study is from The Cochrane Collaboration, the trials involving more than 600,000 women. Their review also emphasized the variation in quality between different studies and noted that the most reliable showed that screening did not reduce breast cancer mortality. However, less rigorous methods introduced bias towards showing that screening did reduced breast cancer mortality. In this sort of trial “less rigorous” relates particularly to the problem of ensuring that the two groups of subjects are truly randomized – i.e. that nothing influences whether a woman is assigned to receive screening mammograms or not. This is much harder than it sounds, mainly because human beings do the assigning so there is always a chance of either a genuine mistake or a flaw in the design of a particular study. One simple example of how the best laid plans … The consent form for a study specifically states that women are assigned, at random, to either the mammography or no mammography group. Women are then examined by a specially trained nurse. However, if these two steps are reversed, assignment may be biased by the findings of the examination. Precisely such a failure to adhere to a protocol has been revealed in at least one study.

Making the liberal assumption that screening reduces mortality by 15% and that over-diagnosis occurs at a rate of 30%, they estimated that for every 2000 women invited for screening over 10 years, one will avoid dying of breast cancer and 10 will be treated unnecessarily. In addition, false alarms will subject 200 women to prolonged distress and anxiety.

All of which explains why, taking everything into consideration, the Big Cheeses recommended that the Swiss abandon mammography screening.

MammogramWhat does the NHS say?

Actions speak louder than words and in the UK women aged 50 to 70 are invited for mammography screening every three years. By way of explanation, the NHS document (NHS breast screening: Helping you decide) says that for every 200 screened about one life is saved from breast cancer. The American Cancer Society recommends screening annually from age 40 – so it’s clear that Britain and the USA are firmly in favour.

You will have noted that the NHS figure of one saved for every 200 screened is seriously at odds with the findings summarized above and they don’t say where it comes from. However, they are clear about the critical point in saying “for every 1 woman who has her life saved from breast cancer, about three women are diagnosed with a cancer that would never have become life-threatening.”

Misplaced optimism

It will be obvious by now that attaching precise numbers to the effects of screening is next to impossible but the overall message is clear. At best screening yields a small reduction in breast cancer deaths but this comes with a substantially greater number of women who are treated unnecessarily – hence the Swiss position that it is ethically difficult to justify a public health program that does more harm than good.

It’s a bit difficult to assess just how knowledgeable women are about the benefits of mammography screening but one study that tried came up with some positively alarming pointers. A telephone survey of more than 4000 randomly chosen females over 15 years of age in the USA, the UK, Italy and Switzerland revealed that a substantial majority believed that (i) screening prevents or reduces the risk of getting breast cancer, (ii) screening at least halves breast cancer mortality, and (iii) 10 years of regular screening prevents 10 or more breast cancer deaths per 1000 women.

A clear conclusion?

Rates of breast cancer mortality are declining. Hooray! And the five-year survival rate in developed countries is now about 90%. Hooray again! It seems probable that this trend is more though improved treatments and greater awareness – leading to early detection – than because of screening. Nevertheless, all that doesn’t alter the fact that where women are offered the choice they need to be as well informed as possible. The weaknesses of the telephone survey are obvious but the implication that misconceptions are widespread indicates that we need to do much better at explaining the facts of mammography screening.


Biller-Andorno N. and Jüni P. (2014). Abolishing mammography screening programs? A view from the Swiss Medical Board. New England Journal of Medicine 370:1965-7.

Independent UK Panel on Breast Cancer Screening. (2012). The benefits and harms of breast cancer screening: an independent review. Lancet 380:1778-86.

Gøtzsche, P.C. and Jørgensen, K.J. (2013). Screening for breast cancer with mammography. Cochrane Database Syst Rev; 6:CD001877.

Domenighetti G, D’Avanzo B, Egger M, et al. (2003). Women’s perception of the benefits of mammography screening: population-based survey in four countries. Int J Epidemiol., 32:816-21.

The Hay Festival

According to the Hay Festival  a recording of my talk ‘Demystifying Cancer’ on Wednesday 28th May should be available on their web site shortly and it can also be heard on the university site. However, I thought it might be helpful to post a version, not least for the for the rather breathless lady who arrived at the book signing session apologising for missing the lecture because she’d got stuck in mud. So for her and perhaps for many others I had the privilege of chatting to afterwards, read on …

 The Amazing World of Cells, Molecules … and CancerOpening pic

One of the biggest influences on my early years was the composer and conductor Antony Hopkins, who died a few days ago. Most of what I knew about music by the time I was 15 came from his wonderfully clear dissections of compositions in the series Talking About Music broadcast by the BBC Third Programme. When he was axed by the Beeb in 1992 for being ‘too elitist’ – yes, they talked that sort of drivel even then – Hopkins might have wished he’d been a biologist. After all, biology must be the easiest subject in the world to talk about. Your audience is hooked from the outset because they know it’s about them – if not directly then because all living things on the planet are interlinked – so even the BBC would struggle to make an ‘elitism’ charge stick. They know too that it’s beautiful, astonishing and often funny – both from what they see around them and also, of course, courtesy of David Attenborough. So it’s not a surprise when you show them that the micro-world of cells and molecules is every bit as wonderful.

The secret of life

What does come as a bit of a shock to most non-scientists is when you explain the secret of life. No, that’s not handing round pots of an immortalization elixir – much better, it’s outlining what’s sometimes rather ponderously called the central dogma of molecular biology – the fact that our genetic material (aka DNA) is made from only four basic units (most easily remembered by their initials: A, C, G and T – humans have over three thousand million of these stuck together). This is our ‘genome’ and the ‘genetic code’ enshrined in the DNA sequence makes us what we are – with small variations giving rise to the differences between individuals. The genetic code carries instructions for glueing together another set of small chemicals to make proteins. There are 20 of these (amino acids) and they can be assembled in any order to make proteins that can be thousands or even tens of thousands of amino acids long. These assemblies fold up into 3D shapes that give them specific activities. Proteins make living things what they are – they’re ‘the machines of life’ – and their infinite variety is responsible for all the different species to have appeared on earth. Can the basis of life really be so simple?

The paradox of cancer

Turning to cancer, a three word definition of ‘cells behaving badly’ would do fine. A more scientific version would be ‘cells proliferating abnormally.’ That is, cells reproducing either when they shouldn’t, or more rapidly than normal, or doing so in the wrong place. The cause of this unfriendly behavior is damaged DNA, that is, alteration in the genetic code – any such change being a ‘mutation’. If a mutation affects a protein so that it becomes, say, hyperactive at making cells proliferate (i.e. dividing to make more cells), you have a potential cancer ‘driver’. So at heart cancer’s very simple: it’s driven by mutations in DNA that affect proteins controlling proliferation. That’s true even of the 20% or so of cancers caused by chronic infection – because that provokes inflammation, which in turn leads to DNA damage.

The complexity of cancer arises because, in contrast to several thousand other genetic diseases in which just a single gene is abnormal (e.g., cystic fibrosis), tumour cells accumulate lots of mutations. Within this genetic mayhem, relatively small groups of potent mutations (half a dozen or so) emerge that do the ‘driving’. Though only a few ‘driver mutations’ are required, an almost limitless number of combinations can arise.

Accumulating mutations takes time, which is why cancers are predominantly diseases of old age. Even so, we should be aware that life is a game of genetic roulette in which each individual has to deal with the dice thrown by their parents. The genetic cards we’re dealt at birth may combine with mutations that we pick up all the time (due to radiation from the sun and the ground, from some foods and as a result of chemical reactions going on inside us) to cause cancers and, albeit rarely, in unlucky individuals these can arise at an early age. However, aside from what Mother Nature endows, humans are prone to giving things a helping hand through self-destructive life-style choices – the major culprits, of course, being tobacco, alcohol and poor diets, the latter being linked to becoming overweight and obese. Despite these appalling habits we’re living longer (twice as long as at the beginning of the twentieth century) which means that cancer incidence will inevitably rise as we have more time to pick up the necessary mutations. Nevertheless, if we could ban cigarettes, drastically reduce alcohol consumption and eat sensibly we could reduce the incidence of cancers by well over a half.

How are we doing?

Some readers may recall that forty-odd years ago in 1971 President Nixon famously committed the intellectual and technological might of the USA to a ‘War on Cancer’ saying, in effect, let’s give the boffins pots of money to sort it out pronto. Amazing discoveries and improved treatments have emerged in the wake of that dramatic challenge (not all from Uncle Sam, by the way!) but, had we used the first grant money to make a time machine from which we were able to report back that in 2013 nearly six hundred thousand Americans died from cancer, that the global death toll was over eight million people a year and will rise to more than 13 million by 2030 (according to the Union for International Cancer Control), rather less cash might subsequently have been doled out. Don’t get me wrong: Tricky Dicky was spot on to do what he did and scientists are wonderful – clever, dedicated, incredibly hard-working, totally uninterested in personal gain and almost always handsome and charming. But the point here is that, well, sometimes scientific questions are a little bit more difficult than they look.

Notwithstanding, there have been fantastic advances. The five year survival rates for breast and prostate cancers have gone from below 50% to around 90% – improvements to which many factors have contributed including greater public awareness (increasing the take-up of screening services), improved surgical and radiology methods and, of course, new drugs. But for all the inspiration, perspiration and fiscal lubrication, cancer still kills over one third of all people in what we like to refer to as the “developed” world, globally breast cancer killed over half a million in 2012 and for many types of cancer almost no impact has been made on the survival figures. In the light of that rather gloomy summary we might ask whether there is any light at the end of the tunnel.

The Greatest Revolution

From one perspective it’s surprising we’ve made much progress at all because until just a few years ago we had little idea about the molecular events that drive cancers and most of the advances in drug treatment have come about empirically, as the scientists say – in plain language by trial and error. But in 2003 there occurred one of the great moments in science – arguably the most influential event in the entire history of medical science – the unveiling of the first complete DNA sequence of a human genome. This was the product of a miraculous feat of international collaboration called The Human Genome Project that determined the order of the four units (A, C, G and T) that make up human DNA (i.e. the sequence). Set up in 1990, the project was completed by 2003, two years ahead of schedule and under budget.

If the human genome project was one of the most sensational triumphs in the history of science what has happened in the ensuing 10 years is perhaps even more dazzling. Quite breathtaking technical advances now mean that DNA can be sequenced on a truly industrial scale and it is possible to obtain the complete sequence of a human genome in a day or so at a cost of about $1,000.

These developments represent the greatest revolution because they are already having an impact on every facet of biological science: food production, microbiology and pesticides, biofuels – and medicine. But no field has been more dramatically affected by this technological broadside than cancer and already thousands of genomes have been sequenced from a wide range of tumours. The most striking result has been to reveal the full detail of the astonishing genetic mayhem that characterizes cancer cells. Tens of thousands or even hundreds of thousands of mutations featuring every kind of molecular gymnastics imaginable occur in a typical tumour cell, creating a landscape of stunning complexity. At first sight this makes the therapeutic challenge seem daunting, but all may not be lost because the vast majority of this genetic damage plays no role in cancer development (they’re ‘passenger’ mutations) and the power of sequencing now means they can be sifted from the much smaller hand of ‘driver’ mutations. From this distillation have emerged sets of ‘mutational signatures’ for most of the major types of cancers. This is a seismic shift from the traditional method of assessing tumours – looking directly at the cells after treating them with markers to highlight particular features – and this genetic approach, providing for the first time a rigorous molecular basis for classifying tumours, is already affecting clinical practice through its prognostic potential and informing decisions about treatment.

A new era

One of the first applications of genomics to cancer, was undertaken by a group at The Wellcome Trust Sanger Institute near Cambridge (where the UK part of the Human Genome Project had been carried out), who screened samples of the skin cancer known as malignant melanoma. This is now the fifth most common UK cancer – in young people (aged 15 to 34) it’s the second most common – and it killed over 2,200 in 2012. Remarkably, about half the tumours were found to have a hyperactivating mutation in a gene called BRAF, the effect being to switch on a signal pathway so that it drives cell proliferation continuously. It was a remarkable finding because up until then virtually nothing was known about the molecular biology of this cancer. Even more amazingly, within a few years it had lead to the development of drugs that caused substantial regression of melanomas that had spread to secondary sites (metastasized).

This was an early example of what has become known as personalized medicine – the concept that molecular analysis will permit treatment regimens to be tailored to the stage of development of an individual’s cancer. And maybe, at some distant time, the era of personalized medicine will truly come about. At the moment, however, we have very few drugs that are specific for cancer cells – and even when drugs work initially, patients almost invariably relapse as tumours become resistant and the cancer returns – one of the major challenges for cancer biology.

It behoves us therefore to think laterally, of impersonal medicine if you like, and one alternative approach to trying to hit the almost limitless range of targets revealed by genomics is to ask: do tumour cells have a molecular jugular – a master regulator through which all the signals telling it to proliferate have to pass. There’s an obvious candidate – a protein called MYC that is essential for cells to proliferate. The problem with stopping MYC working is that humans make about one million new cells a second, just to maintain the status quo – so informed opinion says that blocking MYC will kill so many cells the animal will die – which would certainly fix cancer but not quite in the way we’re aiming for. Astoundingly, it turns out in mice at least it doesn’t work like that. Normal cells tolerate attenuation of MYC activity pretty well but the tumour cells die. What a result!! We should, of course, bear in mind that the highway of cancer therapy is littered with successful mouse treatments that simply didn’t work in us – but maybe this time we’ll get lucky.

An Achilles’ heel?

In defining cancers we noted the possibility that tumour cells might proliferate in the wrong place. So important is this capacity that most cancer patients die as a result of tumour cells spreading around the body and founding secondary colonies at new sites – a phenomenon called metastasis. Well over 100 years ago a clever London physician by the name of Stephen Paget drew a parallel between the growth of tumours and plants: ‘When a plant goes to seed, its seeds are carried in all directions; but they can only live and grow if they fall on congenial soil.’ From this emerged the “seed and soil” theory as at least a step to explaining metastasis. Thus have things languished until very recent findings have begun to lift the metastatic veil. Quite unexpectedly, in mouse models, primary tumours dispatch chemical messengers into the blood stream long before any of their cells set sail. These protein news-bearers essentially tag a landing site within the circulatory system on which the tumour cells touch down. Which sites are tagged depends on the type of tumour – consistent with the fact that human cancers show different preferences in metastatic targets.

These revelations have been matched by stunning new video methods that permit tumour cells to be tracked inside live mice. For the first time this has shone a light on the mystery of how tumour cells get into the circulation – the first step in metastasis. Astonishingly tumour cells attach themselves to a type of normal cell, macrophages, whose usual job is to engulf and digest cellular debris and bugs. The upshot of this embrace is that the macrophages cause the cells that line blood vessels to lose contact with each other, creating gaps in the vessel wall through which tumour cells squeeze to make their escape. This extraordinary hijacking has prognostic value and is being used to develop a test for the risk of metastasis in breast cancers.

The very fact that cancers manifest their most devastating effects by spreading to other sites may lay bare an Achilles’ heel. Other remarkable technical developments mean that it’s now possible to fish out cancer cells (or DNA they’ve released) from a teaspoonful of circulating blood (that’s a pretty neat trick in itself, given we’re talking about fewer than 100 tumour cells in a sea of several billion cells for every cubic millimeter of blood). Coupling this to genome sequencing has already permitted the response of patients to drug therapy to be monitored but an even more exciting prospect is that through these methods we may be moving towards cancer detection perhaps years earlier than is possible by current techniques.

As we’ve seen, practically every aspect of cancer biology is now dominated by genomics. Last picIt’s so trendy that anyone can join in. Songs have been written about DNA and you can even make a musical of your own genetic code, French physicist Joel Sternheimer having come up with a new genre – protein music – in which sequence information is converted to musical notes. Antony Hopkins, ever receptive to new ideas, would have been enthralled and, with characteristic enthusiasm, been only too happy to devote an episode of Talking About Music to making tunes from nature.

A Small Helping For Australia

There’s an awful lot of very good things in Australia. Australians for a start. They’re just so kind, open, welcoming and accommodating it makes touring round this vast land a joy. Not merely do they cheerfully find a way to fix anything you want but they’re so polite that no one’s drawn attention to my resemblance to a scientific version of those reconstructed geriatric pop groups (viz the Rolling Stones or whatever) staggering round the place on their Zimmer frames. And they say wonderful things about my talks – that’s how charming they are!!

Greater bilgy

Greater bilby

Of course, you could say of Australia what someone once said of America and Britain: two nations divided by a common language. In the case of Oz you could also add ‘and by a ferociously competitive obsession with sport.’ So it’s wonderfully not home. Even Easter’s different in that here you get chocolate Easter bilbies rather than rabbits. Bilbies, by the way, are a sort of marsupial desert rat related to bandicoots. The lesser version died out in the 1950s so only the greater bilby is left (up to 20 inches long + tail half as long again) and you have to go to the arid deserts to find those. Not the choccy versions obviously: they don’t do too well in the deserts but they’re all over Melbourne:

Easter bilby

Easter bilby

shops full of ’em – and a lot bigger than the real thing. So, together with the egg avalanche, there’s no limit to the number of calories you can consume in celebrating the resurrection of Christ. Coupled with the glorious fact that there’s scarcely any mention of wretched soccer, all these novelties mean you’re never going to be lulled into thinking you’re still in dear old Blighty (or back in the old country as they delightfully put it here).

Hors D’Oeuvres

Even so there are some marked similarities to make you feel at home. One of the least striking is that most people are overweight. That is, I scarcely notice it, coming from what I regard as the global fat capital, i.e. Cambridge. The stats say that that’s not true, of course. The USA does these things better than the UK. Of course it does. But there’s not much in it. More than two-thirds of American adults are overweight and one person in three is obese. For the UK the prediction is that one in three will be obese by 2020. Currently in Australia 63% of the adult population is overweight, a figure that includes 28% who are obese.

The essential point is that there’s stuff all difference between those countries and the really critical thing is that the rates go on soaring. In the U.S. between 1980 and 2000 obesity rates doubled among adults and since 1980 the number of overweight adolescents has tripled. By 2025 one Australian child in three will be in the overweight/obese category.

Main course

The meat in this piece is provided by a report written by a bunch of Australian heavyweights – all Profs from Sydney or wherever. It has the droll title ‘No Time To Weight’ – do I need to explain that or shall I merely apologise for the syntax? ‘Oh c’mon!’ I hear our Aussie readers protest. ‘We’re going to hell in a handcart and you’re wittering about grammar. Typical b***** academic.’ Quite so. Priorities and all that. So the boffins’ idea is to wake everyone up to obesity and get policy-makers and parliamentarians to do something effective.No Time to Weight report

Why is this so important? Probably unnecessary to explain but obesity causes a variety of disorders (diabetes, heart disease, age-related degenerative disease, sleep apnea, gallstones, etc.) but in particular it’s linked to a range of cancers. Avid followers of this BbN blog will recall obesity cropping up umpteen times already in our cancer-themed story (Rasher Than I Thought?/Biting the bitter bullet/Wake up at the back/Twenty winks/Obesity and Cancer/Isn’t Science Wonderful? Obesity Talks to Cancer) and that’s because it significantly promotes cancers of the bowel, kidney, liver, esophagus, pancreas, endometrium, gallbladder, ovaries and breast. The estimate is that if we all had a body mass index (BMI) of less than 25 (the overweight threshold) there would be 12,000 fewer UK cancers per year. Mostly the evidence is of the smoking gun variety: overweight/obese people get these cancers a lot more often than lesser folk but in Obesity Talks to Cancer we looked at recent evidence of a molecular link between obesity and breast cancer.

Entrée (à la French cuisine not North American as in Main course)

Or, as you might say, a side dish of genetics. The obvious question about obesity is ‘What causes it?’ The answer is both complicated and simple. The complexity comes from the gradual accumulation of evidence that there is a substantial genetic (i.e. inherited) component. Many people will have heard of the hormone leptin, a critical regulator of energy balance and therefore of body weight. Mutations in the leptin gene that reduce the level of the hormone cause a constant desire to eat with the predictable consequence. But only a very small number of families have been found who carry leptin mutations and, although other mutations can drive carriers to overeating, they are even rarer.

However, aside from mutations, everyone’s DNA is subtly different (see Policing DNA) – about 1 in every 1000 of the units (bases) that make up our genetic code differs between individuals. All told the guess is that in  90% of the population this type of genetic variation can contribute to their being overweight/obese.

Things are made more complicated by the fact that diet can cause changes in the DNA of pregnant mothers (what’s called an epigenetic effect). In short, if a pregnant woman is obese, diabetic, or consumes too many calories, the obesity trait is passed to her offspring. This DNA ‘imprinting’ activates hormone signaling to increase hunger and inhibit satiety, thereby passing the problem on to the child.Preg Ob

So the genetics is quite complex. But what is simple is the fact that since 1985 the proportion of obese Australians has gone up by over 10-fold. That’s not due to genes misbehaving. As David Katz, the director of Yale University’s Prevention Research Center puts it: ‘What has changed while obesity has gone from rare to pandemic is not within, but all around us. We are drowning in calories engineered to be irresistible.’


We might hope that everyone gets theirs but for obesity that’s not the way it works. The boffos’ report estimates that in 2008 obesity and all its works cost Australia a staggering $58.2 billion. Which means, of course, that every man, woman and child is paying a small fortune as the epidemic continues on its unchecked way. The report talks formulaically of promoting ‘Australia-wide action to harmonise and complement efforts in prevention’ and of supporting treatment. It’s also keen that Australia should follow the American Medical Association’s 2013 decision to class obesity as a disease, the idea being that this will help ‘reduce the stigma associated with obesity i.e. that it is not purely a lifestyle choice as a result of eating habits or levels of physical activity.’ Unfortunately this very p.c. stance ignores that fact that obesity is very largely the result of eating habits coupled to levels of physical activity. The best way to lose weight is to eat less, eat more wisely and exercise more.

In 2008 Australian government sources forked out $932.7 million over 9 years for preventative health initiatives, including obesity. This latest report represents another effort in this drive. Everyone should read it but, clear and well written though it is, it looks like a government report, runs to 34 pages and almost no one will give it the time of day.

The problem is that in Australia, as in the UK and the USA, all the well-intentioned propaganda simply isn’t working. As with tobacco, car seat belts and alcohol driving limits, the only solution is legislation, vastly unpopular though that always is – until most folk see sense. Start with the two most obvious targets: ban the sale of foods with excessive sugar levels (especially soft drinks) and make everyone have a BMI measurement at regular intervals, say biannually. Then fine anyone over 25 in successive tests who isn’t receiving some sort of medical treatment.

Amuse bouche

I know: I’ll never get in on that manifesto. But two cheers for ‘No Time To Weight’ and I trust the luminaries who complied it appreciate my puny helping hand from Cambridge. In the meantime, not anticipating any progress on a national front, I’m going to start my own campaign – it’s going to be a bit labour-intensive, one target at a time, but here goes!

The other evening I had dinner in a splendid Italian restaurant (The Yak in Melbourne: very good!). And delightful it would have been had I not shared with two local girls at the next table. One was your archetypal tall, slender, blonde, 25-ish Aussie female – the sort you almost feel could do with a square meal. Her companion of similar age was one of the dirigible models. (You’ll understand I wasn’t looking at them at all: I was with my life’s companion so no chance of that – but I do have very good peripheral vision. Comes from playing a lot of rugby). Each had one of the splendid pasta dishes on offer – but, bizarrely, they also ordered a very large bowl of chips. No prizes for guessing who ate all the fries. Miss Slim didn’t have one – not a single one! (OK, by now I was counting). Her outsize friend had the lot. How could she do that with a shining example of gastronomic sanity sitting opposite?

So c’mon Miss Aussie Airship: you know who you are. Let’s have no more of it. Obesity is not a personal ‘issue.’ Regardless of your calorie intake in one meal, your disgraceful behavior ruined a delightful dining experience for me, and quite possibly several other folk within eyeshot, upset the charming waitress and insulted The Yak’s excellent chef. Just think in future: there’s a place in life for chips – but it’s not with everything.


“Obesity: A National Epidemic and its Impact on Australia”

A Very Odd Coincidence

UntitledOne of the great pleasures of swanning round giving talks on biology and stuff to anyone who’ll listen is meeting an amazing range of wonderful folk with a seemingly limitless number of interesting and clever questions, asked either at the end of a lecture or, quite often, when they queue up afterwards to raise personal points or chat about their own experiences. Wide-ranging though the topics are, there’s one word I can’t recall coming up even once. No surprise really. It’s a very rare disease, even though it’s a kind of sub-group of the lung cancers that kill more people every year than any other type – over one and a half million world-wide in 2012 when there were 23 new cases in every 100,000 people. In the USA the incidence is 38 per 100,000, in Australia it’s 27. The very rare form is called mesothelioma – that’s the one where there’s almost always a history of exposure to asbestos. Rarely mentioned though it is, mesothelioma came up after a lecture I gave last week in the sumptuous premises of the Union, Universities & Schools Club, just up the road from Circular Quay in Sydney, when a gentleman from the audience revealed that his wife had contracted the disease and described how he was seeking the next round of treatment options for her. He was kind enough to say that he was a follower of my blog but he hadn’t trawled sufficiently far back to track down a piece I wrote about a lady called Heather Von St. James. To my considerable embarrassment, I couldn’t on the spur of the moment recall what I’d called it (What’s it all about?  Serves me right for trying to be clever with titles: the idea of this one was convey Heather’s determination to have a life with her children and husband in spite of being dealt the really rough hand of mesothelioma). What is it all about? In contrast to the overall incidence figures for lung cancer, mesothelioma afflicts just under one white American in every 100,000, so it is indeed pretty unusual. The UK has the highest rate (top of something then!) but Australia comes second with 2.9 new cases of mesothelioma per 100 000. Since the early 1980s over 10,000 Australians have died from the disease and the rate is still rising. It’s predicted to start falling after 2020 but, even so, a further 25,000 Australians are expected to die from it over the next four decades, the majority being men. Now Sydney, as you may recall, is the largest city in Australia and it’s in New South Wales, so you might predict that, if you were going to run into mesothelioma anywhere outside the UK, Sydney would be the spot. But why? Well, NSW was the first state in Australia to mine asbestos and it produced the bulk of the chrysotile (white) and amphibole forms. Asbestos of whatever type is now classed as carcinogenic but it was not until the end of 2003 that the use of all forms of asbestos was banned in Australia. The hazard remains, however, because of the widespread use that had been made of asbestos for construction, both residential and commercial. The risk can be seen from the near doubling of mesothelioma incidence in NSW between 1987 and 2006, with an even bigger increase being seen in women – attributed largely to second-hand exposure. And the freaky happening? The very next day after my conversation at the Universities Club, and completely out of the blue, I received an email from Heather about what she describes as her ‘life’s mission to educate people about this deadly disease’. Having told the story, perhaps the most helpful thing I can do by way of supporting this remarkable lady is to spread the word of her initiative by advertising the web site.

What Took You So Long?

A long, long time ago – 25 years to be precise – I was lucky enough to work for a few months at The University of New England in Armidale, up on the Northern Tablelands of New South Wales. And jolly wonderful it was too. You could see grazing kangaroos from my lab window and I got to play grade cricket! To anyone who’ll listen I can still describe in vivid detail the scoring of my first run in Oz. We’d won the toss and … (that’s quite enough cricket, Ed).

Equally wonderful is the fact that, in part courtesy of The University of Queensland, I’m going again to Oz – this time to do what I didn’t manage then: visit all the major cities. We begin in Brisbane this week giving a lecture in the U of Q’s Global Leadership series (yes really!), explaining the biology of cancer to an audience of largely non-scientists – at least I hope I’ve got the right brief! We end up in Perth in May having, in between if I can stick the pace, given a variety of talks and seminars to the general public, to schools and to cancer research institutes in Sydney, Melbourne and Adelaide. How good is that? Being invited to warble on about one of your favorite subjects whilst touring Oz? Wow!

What’s new?

All of which makes you think a bit about Father Time and what has happened in the interim. Answer quite a lot, of course. Collapse of communism, collapse and resurgence of Australian cricket (that’s your last warning, Ed) and so on but we’re supposed to inform and enthuse about cancer here so how’s that faired, particularly in Australia? Well, in the year I first followed Captain Cook (watch it, Ed) onto the shore of Botany Bay about 60,000 Australians were diagnosed with cancers of one sort or another and some 30,000 died from these diseases. At that time one in three men and one in four women would be directly affected by cancer in the first 75 years of life.

A Cook

Alastair Cook

And now? This time round the estimated numbers are 128,000 and over 43,000 with one in two men/one in three women discovering they have cancer by time they’re 85. All told, cancer accounts for about three in ten Australian deaths – much the same contribution as heart disease. To add to the gloom the numbers are going up not down so the prediction is 150,000 new cancer cases in 2020.

Not a lot and no surprise

Well, you may be thinking, no change there then – or even I told you so. After all, I’m forever in these pieces elaborating on current cancer stories holding forth about how slow is the progress of science: one step forward, two back, more of a shuffle than a step really, and so on. Or as Martin Schwartz more eloquently puts it, describing science as the art of productive stupidity – being ignorant by choice. This follows almost inevitably from the nature of research because working on what we don’t understand puts us in the awkward position of being ignorant. As Schwartz has it, one of the beautiful things about science is that it allows us to bumble along, getting it wrong time after time, and feel perfectly fine as long as we learn something each time. That’s why I keep telling you to ignore the “great breakthough” newspaper headline dribble – that’s just the hacks trying anything to persuade their editors to give them space to promote themselves.

But wait a mo.

All that sounds consistent with the signs that things in Oz have been going backwards at a rate of knots over the last 20-odd years. But hang on. As ever, bare stats can be a bit misleading (remember what Disraeli said). Thus although around 19,000 more people die each year from cancer than 30 years ago, this is due mainly to population growth and aging – Australian life expectancy has gone up by over four years since 1990 (it’s now 82). The death rate from cancers has fallen by more than 16% and the survival rate for many common cancers has increased by 30 per cent in the past two decades. So that’s great: terrific ad for living in Oz and something of a triumph for medical science.

A sunny side in Oz?

What’s more you can put a positive twist on even the gloomy side of the picture by noting that, if indeed there’s strength in unity, Australia’s trends are much the same as everyone else’s in what we like to call the developed world. Well sort of but there’s a serious negative for Australia Fair, as you might put it, something that sticks out like a sore thumb (or an itchy mole) when you glance at the stats. Between 1980 and 2010 the incidence of skin cancer has shot up in Australia by around 60%. The most common type is non-melanoma skin cancer – usually treatable as it generally doesn’t spread around the body. The nasty version is malignant melanoma – which does metastasize, although is essentially curable if caught before some of its cells escape from the primary site. And the really bad news is that it is now the third most common cancer in Australians and in those aged 15-44 years it is the most common cancer. In 2012, over 12,000 Australians were diagnosed with melanoma and it killed over 1,600. This disease is usually set off by ultraviolet light from sunlight (or sunbeds) damaging DNA (i.e. causing mutations) and you will not have missed the allusion to the fact that people with fair skin (or blue or green eyes/red or blond hair) are most at risk.So the current Oz figures are a bit of a blow to Richie Benaud’s campaign of which I made great play in Slip-Slop-Slap Is Not Enough.


ABCD rule illustration: On the left side from top to bottom: melanomas showing asymmetry, a border that is uneven, ragged, or notched, coloring of different shades of brown, black, or tan and diameter that had changed in size. The normal moles on the right side do not have abnormal characteristics (no asymmetry, even border, even color, no change in diameter).

Meanwhile in the lab?

It’s pretty sobering for me to reflect that it was only a few years before I went to Oz that the first human cancer gene (oncogene) was discovered. That was RAS, detected in human cancer cells in 1982 by Geoffrey Cooper at Harvard, Mariano Barbacid and Stuart Aaronson at the NIH, Robert Weinberg at MIT and Michael Wigler at Cold Spring Harbor Laboratory. Between then and 2003 several hundred more cancer genes were identified in a huge frenzy of molecular stamp collecting. Then came the human genome sequencing project and in its wake analysis of tumours on a scale and level of detail that is almost stupefying and would have been unimaginable before 2003. To appreciate the mountain of cancer data that has been assembled over that period, screen the literature data base for research papers that have ‘RAS’ in the title: that is, contain significant info relating to that gene. Answer: 76,000. That’s seventy-six thousand separate pieces of research that have made it through all the peer review and editorial machinery to see the light of day in print. And RAS, massive player though it is, is not the biggest. Do the same check for a gene called P53 and the number is: over 145,000!!

Confused? The plot so far …

First up we noted that the cancer burden in Oz has got a lot heavier over the last 25 years, then we reminded you that advances in science are of the snail-like variety – so you shouldn’t be surprised when things seem to go backwards. But, flipping to the other hand, we trotted out another set of figures saying things have actually got much better (life expectancy and cancer survival rates have steadily climbed). Though, switching hands again, melanoma’s gone through the roof. However, going back to the first hand, if we can still locate it, we noted the massive explosion in the facts mountain of cancer biology for which the blue touch paper was only lit about 25 years ago.

And your parliamentary candidate is …

What with all this sleight-of-hand, flip-flopping and U-turning, it occurs to me that I’m shaping up rather well as a prospective politician. I’m quite taken with the idea, especially as if I stood as an MP in my own constituency I’d be up against Andrew Lansley who, as you’ve probably forgotten, was once upon a time Secretary of State for Health. Being a virtuous and helpful soul, when Betrayed by Nature came out I sent him a copy as a gift, a freebie, – figuring that, as a career civil servant and politician who’d become responsible for the nation’s health, he might find it useful to read a basic primer on something that was killing 150,000 UK citizens every year. Thoughtful, you’d say? Indeed. Did I expect to find him on my doorstep next day gushing gratitude and thirsting for more knowledge? Maybe not, even though he only lives round the corner and we have actually met in the dim past. But at least one might have received a note – a one line email, perhaps – from his PA, who can scarcely be too busy to be polite. But no. Nothing. Zippo. So I came up with a brief sentence that summarised my take on this example of voter wooing, or indeed plain good manners, but I can’t remember it now – for the best perhaps. What is it the Bible says about getting narked? Something along the lines of “whoever says, ‘You fool!’ shall be liable to the hell of fire.”

So thank heavens we’ve side-stepped that but nevertheless, Andrew, it really would be a joy to give you a bloody nose – electorally speaking, of course – so let’s just give those credentials one more buffing. We started by lowering your expectations of science with the reminder that things proceed at a snail’s pace {you do realise that common analogy is very unfair on snails? Scientists have shown they can bowl along at a metre an hour (yippee, we do discover things!) – not much slower than your average supermarket trolley-pusher, but here’s the thing. Snail’s pace means they can get round the garden in one night. That’s the whole of their world covered in one go – without mechanical assistance!! Not so slow after all, eh?}. But the flip side is that the genomic era has already seen the development of a number of drugs that are effective against malignant melanoma. They’re not perfect but at least they take us a step further in dealing with this cancer once it has spread around the body.

And the message?

(That’s quite enough politics, Ed). OK. Let’s abandon a promising career and go back to being a scientist with a typically punchy summary. Australia’s wonderful but when it comes to cancer it’s not much different to any other rich country (not really a flip that, just a statement of fact). Folk are living longer so, of course, more of us will ‘get’ cancer but we seem to think that longevity buys us more time to smoke, booze, burn ourselves pink and eat crappy food. Medical science is doing wonders in detection and treatment: at nearly $400 million a year on cancer research, almost a quarter of all health research expenditure in Australia, it jolly well should. But if we don’t do more to help ourselves the cancer burden is going to overwhelm health resources not just ‘down under’ but all over.


Schwartz, M.A. (2008). The importance of stupidity in scientific research. J Cell Sci 2008 121:1771; doi:10.1242/jcs.033340


Avert The Eyes

P.G.Wodehouse’s injunction is perhaps appropriate because this site is really for entertaining non-biologists whilst helping them to keep up with the astonishing advances in cancer research.

This piece, we have to admit, is more of a professional plug. No, it IS a professional plug but I blame my publisher who sent me the review below with the instruction to be more dynamically self-promoting. So, with apologies for appearing to be auditioning for the oldest profession, I give you:

A review from the esteemed Choice Reviews Online of America of my textbook Introduction to Cancer Biology.

Choice Review ItCBIf anyone has friends or rellos studying biology, doing medicine or involved in teaching please pass on!!

Oh, and ask them to put comments (only 5-star of course) on Amazon!!

Next time we’ll get back to what this blog’s supposed to do!