Open Wide for Pasty’s Throat

 

Once upon a time (1903 to be exact) a very rich Adelaide family acquired a new member in the form of a little boy whom they christened Norman. Most of the family were doctors and, so well-heeled were they, when young Norm reached the age of 10 they clubbed together and sent him off to the Old Country – and not just to any bit of Merrie England but to Eton (the school, of course, not the rustic parish, generally held to be the most expensive of all – fees currently about £36,000 a year, not counting extras). Norm never returned: South Australia’s loss was Britain’s gain.

We all know what happens to kids that go to Eton – but our Adelaide man was different. For one thing he was very bright and for another he had his family’s love of medicine. He ended up specializing in the thorax – the bit between the neck and the tummy that includes the oesophagus, commonly known as the foodpipe or gullet. Eton probably helped get him started but, even more usefully, some bright spark there gave him the nickname ‘Pasty’ – so great an improvement on Norman that it stuck for life. ‘Pasty’ Barrett ended up as a consultant at St. Thomas’ Hospital where, in 1947, he successfully repaired a ruptured oesophagus – a surgical first for a hitherto fatal condition.

Shortly after that, in 1950, he described finding that sometimes the cells lining the gullet change in appearance, switching from multiple layers of flat cells to a single layer of cells that look like those found in the intestine. We know now that this change is caused by acid from the stomach being squeezed up into the oesophagus. Occasional regurgitation is called heartburn but when it’s persistent it becomes gastric reflux disease – and in about 10% of those cases sustained irritation caused by the stomach juices upsets the cells lining the gullet and they undergo the change to what is now called Barrett’s oesophagus.

Who cares about Barrett’s?

Well, we should all at least take note because a few percent of those with Barrett’s oesophagus will get cancer of the oesophagus, which is now the sixth most common cause of cancer-related death world-wide. Oesophageal cancer has become more common over the last 40 years, men are more prone to it than women and it kills about 15,000 people in the USA each year and nearly 8,000 in the UK. It’s very bad news. Most cases aren’t discovered until the disease has spread and it is then more or less untreatable. The prognosis is dismal: the five-year survival figure is barely 15%. Part of the problem is that the main sign is pain or difficulty in swallowing, often ignored until it is too late.

For many years the only way of finding abnormal tissue was by an endoscopy – a tube with a camera pushed down the throat – both unpleasant and expensive. There has, therefore, been a desperate need for an easy, cheap, non-invasive test to screen for Barrett’s oesophagus.

Professor Rebecca Fitzgerald

     Professor Rebecca             Fitzgerald

Pill on a string

Enter Rebecca Fitzgerald, a member of the Department of Oncology in Cambridge and a consultant at Addenbrooke’s Hospital, with a brilliantly simple development from earlier attempts to screen the lining of the gullet. The patient swallows a kind of tea-bag on a string which is then pulled up from the stomach. The ‘tea-bag’ is actually a capsule about the size of a multi-vitamin pill containing a sort of honeycomb sponge covered with a coating that dissolves in a few minutes when it reaches the stomach. As the sponge comes up it picks up cells from the gullet lining (about half a million of them) that can then be analysed. The whole gizmo’s called a ‘Cytosponge’. It works with no problems and because it collects cells from the length of the gullet it gives a complete picture, rather than the local regions sampled in biopsies.

Pill on a string

                 Pill on a string

Cytosponge (left) and being drawn up the gullet (right)

       Cytosponge (left) and being             drawn up the gullet (right)

 

 

 

 

 

What we’ve learned

The hope was that the cells picked up by Cytosponge could be sequenced – i.e. their DNA code could be obtained – and that this would reveal the stages of oesophageal cancer development and hence whether a given case of Barrett’s would or would not progress to cancer. The phases of Barrett’s oesophagus involve a change in the shape of cells lining the tube (from thin, flat cells called squamous epithelial cells to taller columnar cells resembling those in the intestine). This change is called metaplasia: the abnormal cells may then proliferate (dysplasia). If this stage can be detected it’s possible to remove the abnormal tissue by using endoscopic therapy before the condition progresses to full carcinoma.

Remarkably, whole-genome sequences from Barrett’s and from oesophageal carcinoma showed that multiple mutations (changes in DNA sequence) accumulate even in cells that are over-proliferating but look normal. The picture is similar to the ‘battlefield of hundreds of competing mutant clones’ in normal eyelid skin that we saw in The Blink of an Eye.

As the condition progresses the range of mutations increases: in particular, regions of DNA are duplicated – so that the genes therein are present in abnormal numbers. Typically there were 12,000 mutations per person with Barrett’s oesophagus without cancer and 18,000 mutations within the cancer.

Even from this mayhem there emerged mutation patterns (changes in the letters of the DNA code, e.g., A to a G or C to a T) characteristic of the damage caused to the cells lining the oesophagus by splashing stomach acid. These ‘fingerprints’ were found in both Barrett’s and oesophageal cancer – consistent with them being very early events – parallelling the specific mutations in lung cancer caused by tobacco carcinogens.

But …

The great hope was that the spectrum of mutations would identify precursors to cancer and hence those patients requiring treatment. In fact these horribly heterogeneous tissues – a real genetic gemisch – show surprisingly little mutational overlap between Barrett’s oesophagus and oesophageal cancer.

However, it’s possible to take the cells collected by the Cytosponge and screen them for the presence of specific proteins (using antibodies) and it turns out that one in particular, TFF3 (Trefoil Factor 3), provides a highly accurate diagnosis of Barrett’s oesophagus. In addition, although the genetic changes that occur during the progression from Barrett’s to cancer are complex, mutations in one gene (P53 – the ‘guardian of the genome’) are common in pre-cancerous, high grade dysplasia and thus provide an indicator of risk.

All of which means that we haven’t ‘conquered’ oesophageal cancer – but thanks to these remarkable advances we have a much better understanding of its molecular basis. Even more importantly, it’s possible to detect the early stages – and do something about it.

AND … whilst making a major contribution to all this, Rebecca Fitzgerald very kindly found time to make suggestions and provide additional information for this piece.

References

Ross-Innes, C.S., Fitzgerald, R.C. et al. (2015). Nature Genetics 47, 1038-1046.

 

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Treading the Boards

If I’d asked my friends whether I should consider a debut on the West End stage I know what they would have said. So instead this week I did Cancer Crystal Ball for Robin Ince’s Christmas Science Ghosts at the Bloomsbury Theatre.

Here’s what Bruce Dessau of the London Evening Standard made of proceedings, although the review scarcely does justice to an astonishingly eclectic show!

Bruce Dessau:

Most comedy gigs offer audiences something to laugh about. Robin Ince’s annual Bloomsbury package also offers something to think about. This year’s five-night stint mixes stand-ups and scientists. With a seasonal nod to A Christmas Carol, last night’s show looked at the future.

Ince compered briskly, doing little more than pithy impressions of Brians Blessed and Cox. Having booked a preposterously epic 16 acts he exercised impressive restraint to keep the gig under three hours.

Among the experts doing some crystal ball-gazing were Ben Goldacre, who mounted a persuasive argument for more testing of statins, and cancer specialist Robin Hesketh, who had blood taken onstage — a first for a comedy gig.

Swotty storyteller Josie Long invited fans to do her A-level maths test, while Stewart Lee read from a letter supposedly penned by his 11-year-old self about the future: “There will be even more TV channels … seven. One will be just firework displays.” Joanna Neary’s Björk impersonation skirted around the futuristic theme but was so accurately nutty it hardly mattered.

It was not only the comics who raised a laugh. If you ever wondered what it would be like if Eminem rapped about the brain, catch Baba Brinkman, who closed proceedings by freestyling about neuroscience with his wife Heather Berlin. Conclusive proof that it is possible to be funny and clever.

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.’

Desserts

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.

Reference

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

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.

220px-Melanoma_vs_normal_mole_ABCD_rule_NCI_Visuals_Online

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.

Reference

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

 

A Refresher from the BBC

Regular readers will probably feel they know all this stuff but if you’re interested in a spirited and wide-ranging conversation about cancer with the wonderful Jeremy Vine on his BBC Radio 2 show yesterday you can find it at:

http://www.bbc.co.uk/programmes/b03yn0jd about 1 hour 10 min from the beginning.

BBC Radio 4As ever, any arising thoughts, questions or comments appreciated – apart, of course, from the below the belt: “Judging by the photo it’s a good job it was radio not t.v.”

 

The Things You Find

Robert Peston is a journalist familiar to followers of the BBC news for his idiosyncratic accounts of events in the world of business and economics whose speech style has been described as “excruciatingly hard to listen to”. I quite like it – not enough to imitate, mind you – but just in short bursts I love it, mainly because it carries the innuendo of ‘what a bunch of prats these people are’ – or is that just my default position when it comes to the world of high finance?

All that is slightly beside the very distressing point that his wife, the writer Siân Busby, died in September 2012 from lung cancer after a long illness. I suppose everyone finds their own ways of dealing with the most awful of tragedies. For Peston one response was to realize that most people know almost nothing about cancer which means that, when they have to face it in themselves or in their near family – as almost everyone has to – they’re very ill-equipped. The obvious place to start in rectifying this ignorance of both our own basic biology as well as what can go wrong to make cancer is in schools but a few enquiries revealed that there is, somewhat disgracefully, no centralized system in the UK for enabling scientists to talk to children.

He therefore set about creating such a system: a database of scientists willing to go to schools to talk about their area of interest that was christened “Speakers for Schools.” So dynamic was he that this revolutionary idea actually filtered through to the Vice Chancellor of the University of Cambridge, Professor Sir Leszek Borysiewicz, who, bless him, promptly signed up to Peston’s plan. Now far be it for me to convey that I’m on hob-nobbing terms with Boris but it did so happen that at a booze-up for folk who’d contributed to Cambridge’s Science Festival we got chatting and, as he’s a medic by background, the conversation naturally turned to telling the world about cells, molecules and cancer and before you could say ‘have another canapé VC’ I was signed up too.

So it came to pass that I found myself this week motoring to Bedford and my first “Speakers for Schools” gig. In so far as I was thinking about anything, apart from whether I might make it back to Cambridge for lunch, I suppose I had in mind that I know I give a decent and at least mildly entertaining spiel so that would be fine. Otherwise, inevitably, there was the lurking thought that Bedford is one of those places you try to go round, and not just to avoid its dire traffic – but then, if everywhere was as idyllic as Cambridge the world would be a tad tedious.

At which point something totally unexpected happened. After extracting myself from a housing estate or two, there stood before me Bedford Academy, formally opened in September 2010. Specializing in science and technology,  the school has been completely rebuilt at a cost over £27 million – and my goodness that shows. It’s just a spectacular building.

RH at Bedford Academy

A group of Bedford Academy students together with their science teacher. There’s also a bloke who’s wandered over from Cambridge, though you may have trouble spotting him.

The audience was great – they really tried to contribute to the lecture and asked good questions and were hugely appreciative, after which a group of sixth formers showed me round the science department. And stunning it was. If you were trying to persuade someone to go into teaching you couldn’t come up with a more attractive set-up. A wonderfully open layout with lots of comfortable communal space and every state-of-the-art support you could ask for. Their students are going to find a few of our universities a bit of a let-down. So all told I came away thoroughly uplifted (and yes, that is from Bedford!). The next time I come across doom-laden tales of British education I’ll recall my unexpectedly enjoyable morning at Bedford Academy where the final touch was that all the pupils I met, as well as being quietly enthusiastic, could not have been more charming and polite. And I made it back for a lunch  the more enjoyable for the thought that we are getting some things right in our schools.

 

Spinning Out In Control

In Signs of Resistance and Seeing the Invisible we emphasized two things well known to the interested, namely that most cancer deaths occur because cells spread from the original (primary) to secondary sites (metastases) where they are very difficult to treat, and that this places massive importance on early detection. Many will also be familiar with the currently used methods for tumor detection – X-ray based imaging (as in mammography and CT scans) and PET that detects injected radioactive tracers. The problem is that these are not sensitive enough to detect growths smaller than about 1 cm in diameter – and by that point there are several hundred million cells in the tumor and some may already have metastasized.

Tumor cells spread around the body by detaching from the primary and getting into the circulatory system and it’s beginning to look as though quite literally tapping into the circulation may revolutionize cancer detection. Seeing the Invisible showed how silicon chip technology can be used to retrieve circulating tumor cells (CTCs) by getting them to stick to targets anchored in a flow cell. Although this is hugely promising, another very recent advance may be even more effective. This uses centrifugal force to separate cells in blood on the basis of their size – that’s the one that pushes outwards on objects rotating about an axis. Because force is proportional to mass and tumor cells are larger than red blood cells and most white cells, this effect can be used to extract CTCs from fluid being pumped around a spiral microchannel. The spirals are made from a silicon-based polymer (the same stuff that’s used for contact lenses) stuck on glass slides and they have two outlet channels. Their shape creates two-counter rotating vortices in the fluid that exert a drag force on the cells so that bigger (heavier) tumor cells can be selectively directed to one of the outlets. Typically red blood cells are about 6 microns (one-millionth of a metre), white cells 8-14 microns and CTCs 16-25 microns in diameter.

The vortices are named after a Cambridge chappie, William Dean, who worked on flow patterns in curved pipes and channels and you can look up Dean vortices on the internet for images of these in action.

MCF7s right, rest left

In this picture of the two exits from a spiral microchannel breast cancer cells are carried to the right (yellow arrows) whilst all the other types of blood cell funnel left.

This method appears to be remarkably efficient in that over 90% of tumor cells (10-100 cells per ml of blood) can be separated from 99.99% of red cells (5,000,000 per ml) and 99.6% of white cells (10,000 per ml).

References

Hou, H.W., Warkiani, M. E., Khoo, B.L., Li, Z.R., Soo, R.A., Tan, D.S.-W., Lim, W.-T., Bhagat, A.A.S., and Lim, C.T. (2013). Isolation and retrieval of circulating tumor cells using centrifugal forces. Scientific Reports 3, Article Number: 1259. DOI: 10.1038/srep01259.

Bhagat, A.A.S. et al., 15th International Conference on Miniaturized Systems for Chemistry and Life Sciences October 2-6, 2011, Seattle, Washington, USA

Tiny But Perfectly Formed

Regular readers (assuming the plural is appropriate) will know that our remit is to explain new developments in cancer. So numerous, multi-faceted and remarkable are these that we have been obliged in the past to offer explanation, if not apology, for surfeits of superlatives. So there is no requirement to step outside the admittedly broad acres of cancer biology to inform, astonish and amaze. Nevertheless, a change is said to be as good as a rest and for this we will make a rather pathetic bipedal excursion into the six-legged world that makes up, we estimate, more than 90% of all the different life forms on earth.

Meet the family

Yes, it’s the insects that have caught our eye – specifically a species of planthoppers by the name of Issus coleoptratus. They’re members of the Issidae family which alone includes about 1000 distinct species – a staggering thought, although if you bear in mind that there are approaching 10 million insect species around, clearly each family needs to contribute its bit. The Issidae was first described by one Maximilian Spinola – who was indeed descended from the celebrated Genoese family, pre-eminent during the high-water period of that city-state between the 12th and 14th centuries.

Issus nymph. Photo by Malcolm Burrows

Issus nymph. Photo by Malcolm Burrows

The Issidae are common in Britain and Europe but they’re unusual in that, although they still have wings, they’ve lost the ability to fly. But if you didn’t know already you’ll have guessed that they’ve made up for this in terms of getting around by working hard on their leg muscles. So much so that the nymphs (which, delightfully, is what the insect folk call the immature form – just a couple of millimeters long before it metamorphoses into a grown-up) can jump up to 40 cm – more than 100 times their length.

As you might suppose, to achieve such calisthenic feats the nymphs need their back legs to be as coordinated as possible – not least to prevent them veering off in random directions, rather like the man-powered flight loonies who jump off London Bridge.

Electrical v. mechanical

Somewhat surprisingly, it’s emerged that electrical signalling via the nervous system isn’t good enough for this coordination. Malcolm Burrows and Gregory Sutton from Cambridge and Bristol Universities, respectively, have shown that to get both legs to kick off within 30 microseconds, the Issus make interacting gears that, in effect, lock their legs together. That’s an astonishing finding because although we know that proteins can do anything – form cables, bridges and travelators as well as pumps, rotating flagella and even motors (such as the ATP synthase of mitochondria) – a toothed wheel is a first. Even against a backdrop of such amazing, multi-component machines, it’s a staggering sight – the more so as Burrows and Sutton estimate that on take-off the gears whiz round to the tune of over 33,000 revolutions per minute!

Gearwheels of the flightless planthopper insect Issus

Gearwheels of the flightless planthopper insect Issus

There are, of course, other great leapers in the insect world but those that have been examined use friction for synchronization – grippy legs if you like. So it’s a bit of a mystery that this planthopper has come up with such a sophisticated locking system. But that’s not the only remarkable thing about these little chaps because as they grow into adolescents they go through a kind of moulting process in which they shed their exoskeleton for an upgrade – including progressively bigger gears. How incredible is that? But having gone to all this trouble the final amazing twist is that the gears vanish when nymph becomes adult! So for the rest of their lives they too rely on non-slip legs.

Burrows and Sutton hazard that, although mechanical gears are the most efficient way of linking both legs at kick-off, they carry a big risk for prolonged use – damage a tooth and the chances are you’ll end up on someone’s menu. So better a somewhat less efficient system that is not liable to failure. Exactly how I justified driving an Austin A35 for many years.

One Giant Leap For Mankind

So these marvellous juveniles, less than half a centimeter long, pull off a trick equivalent to me jumping the length of the Melbourne Cricket Ground with so much to spare I land somewhere in the stands. No question, it gives a new meaning to the term ‘jumping genes’ that, you may recall, are stretches of DNA that can be shifted around the genome. They were discovered 60-odd years ago in maize by Barbara McClintock who came from Hartford, Connecticut and remains the only woman to win the Nobel Prize for Physiology or Medicine on her own.

How Did You Know That?

Well, the thing is we now know that these athletic DNA fragments can sometimes land in the wrong place – meaning that they disrupt normal genes. If that sounds suspiciously like a type of mutation it is, and the insertion of a jumping gene can act as a cancer-promoter. By which ingenious piece of circuitry we bring ourselves back to cancer – where we should be – having nevertheless thoroughly enjoyed our visit to the insect Olympics.

References

Burrows, M. and Sutton, G. (2013). Interacting Gears Synchronize Propulsive Leg Movements in a Jumping Insect. Science 341, 1254-1256.

http://www.extremetech.com/extreme/166493-evolution-delivers-the-first-mechanical-gear-found-in-a-living-creature

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!