Heir of the Dog

I’ve probably in the past owned up to causing generations of students to do that raised eyebrow thing, familiar to all parents of teenagers, that, far more pointedly than words, says ‘The old boy’s finally lost it.’ Indeed I may well have a bit of a causative repertoire but one that unfailingly works is revealing that, even after a life in science, I still get ‘Wow’ moments every couple of months or so when I read or hear of some new discovery, method or insight that brings home yet again the wonder of Nature – or has you asking ‘Why didn’t I think of that?’ (The response to that one’s easy, by the way, so please don’t write in).

A common question

The most recent of these jaw-dropping events relates to a question often asked about cancer: ‘Can you catch it from someone else?’ In other words, can cancers be passed from one person to another by infection, much as happens with ’flu? The answer’s ‘No’ but, as usual in this field, even the firmest statement can do with a little explanation. The first point is that the ‘No’ is true even for 20% or so of cancers that are actually started by microbial infection – what you might call ‘bugs’ – bacteria, fungi, and viruses. One such, the bacterium Helicobacter pylori, can cause stomach ulcers that may lead to cancer. Those even smaller bugbears, viruses (typically one one-hundredth the size of a bacterium), are responsible for much of the cervical and liver cancer burden world-wide. Oh, and there’s a little, single-cell parasite (Trichomonas vaginalis), the most common non-viral, sexually transmitted infection in the world that, in men, can cause prostate cancer. But these infections are not cancers even though they may be an underlying cause – bacteria through prolonged inflammation and effects on the immune system and viruses by making proteins that affect how cells behave. Only when these perturbations cause genetic damage – i.e. DNA mutations – do you have a cancer. Which is why the answer to the original question is ‘No.’

There’s always one

Well, two in this case – and, given that we’re talking about cancer, you won’t be surprised that there are some oddities. They’re not exceptions to the ‘No’ answer because they occur in other animals – not in humans – but, in each, tumour cells are directly transferred from one creature to another – so it is cancer by infection. One such contagious tumour occurs in the Tasmanian devil. It’s transmitted by biting, an activity popular with these little chaps, and it gives rise to a particularly virulent facial tumor, eventually fatal because it prevents eating. To counter the probability that Tasmanian devils will become extinct in their native habitat, a number of Australian sanctuaries have breeding programmes aimed at setting up a disease-free colony on Kangaroo Island, South Australia.

TDs

Tas D

 

 

 

 

 

Tasmanian devils – cancer-free – Lone Pine Koala Sanctuary, Brisbane

A very similar condition in dogs known as canine transmissible venereal tumour (CTVT: also called Sticker’s sarcoma), mainly affects the external genitalia. First spotted in the nineteenth century by a Russian vet, it too is spread either by licking or biting and also through coitus. Dogs with CTVT can now be found on five continents and, from DNA analysis, we’ve known for some time that – remarkably – all their cancers are descended from a single, original tumour cell that appeared many years ago. They’re like one of those cell lines grown in labs all over the world, except they’ve been going far longer than any lab – with man’s best friend doing the cultivating.

So what is new?

Elizabeth Murchison and colleagues at The Wellcome Trust Sanger Institute, Cambridge have just produced the first whole-genome sequences of two of these tumours – from Australia and Brazil (an Aboriginal camp dog and a purebred American cocker spaniel). These confirmed that all CTVTs descend from a single ancestor who, they estimated, was trotting around about 11,000 years ago. The last common relative of the two dogs whose tumours were sequenced lived about 500 years ago, before his descendants went walkies to different continents.

And the ‘Wow’?

We already had a pretty good idea of how CTVTs have been handed down. In this paper the really amazing bit came in the detail. The authors estimated roughly how many mutations were present in each tumour. Answer: a staggering 1.9 million. And it’s staggering partly because it’s only slightly less than a change every 1,000 units (bases) in dog DNA but it’s truly awesome when you note that it’s several hundred times more than you find in most human cancers. We’re getting used to the idea of thousands or tens of thousands of mutations turning up in human cancer cells with associated gross disruptions of individual chromosomes. But these canine cancers display genetic mayhem on a massive scale – perhaps best visualized by comparing their chromosomes with those of a normal dog using a method that labels each with a different colour. A glance at the two pictures tells the story: all the cancer chromosomes from one of the tumour-bearing dogs (on the right) have been shuffled as if in some molecular card game. The full range of colours can still be seen, but of the normal pattern of 39 pairs of identical segments of DNA (left) there is no sign.

Two dogs chromos

Dog chromosomes. Left: normal; right: CTVT

(from Murchison, E.P. et al. (2014) Science 343, 437-440)

It seems incredible that cells can survive such a shattering of their genetic material – a state called ‘genetic instability’ because, once DNA damage sets in, mutations usually continue to accumulate. These cancers are uniquely bizarre, however, because although their genomes have been blown to smithereens, not only do the cells survive but they’ve continued suspended in this surreal state for centuries. They’re genetically stable – it really is the cellular equivalent of balancing an elephant on a pin.

‘Wow’ Indeed – but so what?

So like me you’ve been blown away by these discoveries but you may be asking, apart from the excitement, what’s in it for us humans? Well, there’s one other very strange thing about these dog cancers. Infected animals do indeed develop the most unpleasant, large tumours – but most of them are eventually rejected by the host dog. That is, its immune system gets to work to eliminate them – and after that the dog is immune to further infection. We are only just beginning to find ways of boosting the human immune system so that it can attack cancers and maybe, just maybe, we can extract from the stable chaos of the CTVT genome the secret of how they provoke rejection – and maybe that will guide human treatments.

Reference

Murchison, E.P. et al. (2014). Transmissible Dog Cancer Genome Reveals the Origin and History of an Ancient Cell Lineage. Science 343, 437-440.

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A Visit to Bywong Road

Regular readers (how freely we use that expression!) will know we were due to depart for the Southern Hemisphere and so might guess from the title of this piece that we’ve at least got as far as Singapore. But actually we’re not as unworldly as you might suppose and in fact we’ve made it to beautiful Brisbane and even given the Global Leadership lecture that was the prime mover for the trip. And jolly good it was to be able to speak in The Customs House, a wonderful building that in 1889 when it was opened must have looked a bit like a cathedral – albeit dedicated to mercantile trade and the enlargement of the British Empire. Today it’s Corinthian columns are dwarfed by the constellation of fantastic skyscrapers that now make up downtown Brisbane – which makes it a really special place to step into. It was also a great privilege for me to talk to a full house that was so appreciative I think I was still answering questions two hours afterwards when the staff were on the point of carrying us outside to continue our discussions on Queen Street while they went home.

Customs House from the Brisbane RiverCustoms House from the Brisbane River

Even if you’ve never been to Australia you’ll know it’s a land of surprises and while I was still thinking nothing could upstage my evening in Customs House, next morning I found myself in front of 200 students at the QASMT school in Toowong, a delightfully hilly and leafy suburb of Brisbane. The somewhat daunting plan was to talk to them for an hour, persuading them that biology is fantastic and telling them a bit about cancer. Daunting hardly does it justice in that I’d never tried to keep that many school kids entertained before (not even when, for a mercifully short time, I was actually a teacher in Liverpool did I get confronted by classes of that size [as an historical aside, the first time I walked into a school classroom as a teacher I found before me 50 (exactly) nine year olds, of mixed ability and desperate backgrounds. So nowadays, with even the biggest UK class size being seemingly 30, the teaching game must be a doddle].

 4QASMT School, Bywong Road, Brisbane

My teaching experience could hardly be more different to what greeted me at the school on Bywong Road. Entry is via the school’s exam and they follow the International Baccalaureate (IB) Diploma Programme which means they teach a broad curriculum, albeit with a strong emphasis on science (their acronym stands for Queensland Academy for Science, Mathematics and Technology). The buildings are extensive, new, include (as their blurb puts it) university-standard science laboratories and, all told, provide a wonderfully attractive environment. However, what made my visit the highlight of Australia so far were the pupils. Favourable impressions are certainly helped by the Australian predilection for school uniforms and at QASMT all students are required to wear the Academy’s uniform. And very smart they look too. Without being regimented, they appear comfortable, neat and completely professional. I know that probably sounds like an old fogey talking but, if so, we have to conclude that there are a few of those determining school policy in Australia – and long may they prevail!

I’m not sure whether my 200 were entertained but boy were they attentive and full of great answers as we went along. After my main talk the head girl and boy made a delightful presentation after which – perhaps the best bit of all – I sat for an hour or so in the sunshine chatting to a charming and wonderfully polite group of boys and girls who were just full of interesting, thoughtful and clever questions.

I arrived at Bywong Road in a state of some trepidation but left marvelously uplifted, feeling much privileged to have spent a few hours in the world of these inspiring young Australians.

 

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