One Book Good, Two Books Better?

Well, from the author’s viewpoint it’s a no-brainer in the regrettable modern argot but, aside from that lone and far from impartial figure, it probably depends on who’s doing the reading. So let’s get the basics clear: this blog is about current topics related to cancer and the idea is to follow – albeit even more colloquially – the style and content of Betrayed by Nature (that’s Book 1, by the way).

Book 2 has just come out and it’s a textbook. The title tells all: Introduction to Cancer Biology – written to take students from high school/sixth form to degree level in cell & molecular biology and cancer – or indeed anyone else who moves into the field from what’s sometimes deferentially referred to as the ‘hard sciences’ (that means, for example, folk like physicists and maths whizzos who decide to take on the challenge of disentangling cancer).

So, of course, the Christmas message is “Read both” – but, being serious for a mo, only take on Book 2 if you are (or at least thinking of becoming), ‘a serious scientist’ and, contrary to what you may be told, there aren’t many of them – we really are jolly souls and labs resound to shrieks of mirth and girlish giggles (and that’s just the blokes).

So by the end of Book 2 we’ve met a lot of genes and much of the complexity of cancer is laid bare in grizzly detail, whereas in BbN the aim is to tell the essential story in entertaining style. Even so, both books were written with the same guiding principle: the way our cells behave – and misbehave – is a wonderful, compelling tale and they come together as a work of art – a human being. The challenge for the author is to convey all that through the words you put down on the page.

I’m not the first scientist to recognise the problem. Max Born (who won the 1954 Nobel prize in physics for his work on quantum mechanics – he was great mates with Werner Heisenberg – of uncertainty fame) wrote “To present a scientific subject in an attractive and stimulating manner is an artistic task, similar to that of a novelist or even a dramatic writer. The same holds for writing textbooks.” Couldn’t have put it better Max.

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Slip-Slop-Slap Is Not Enough

I’ve always credited Richie Benaud, the wonderful Australian cricketer and commentator, with the Slip-Slop-Slap slogan (I know – it was really thought up by some bright spark in Cancer Council Victoria who got Sid Seagull to sing it). But Mr. B ingrained it into cricket lovers world-wide as a mantra for preventing them getting skin cancer (slip on long sleeved clothing, slop on sunscreen and slap on a hat, you see) – the main preventable cause of melanoma being excessive exposure to ultraviolet (u.v.) radiation, most of which comes from the sun. And maybe it worked for the cricket fraternity who are, by definition, very smart cookies. Unfortunately in Australia the number of new cases of melanoma – the most lethal form of skin cancer – goes on increasing (over 11,000 in 2008) and it’s a serious UK problem too with 13,000 new cases in 2012 (the second most common cancer in 15 to 35 year olds) and over 2,200 deaths.

     

Avoid sunburn …                     Play cricket …                     … for Cambridge!!

Finding a major melanoma mutation

In 2003 sequencing of the human genome was completed and it wasn’t long before Mike Stratton and his colleagues at The Sanger Centre near Cambridge had applied the knowledge and methods of that great triumph to melanoma – a form of cancer about which virtually nothing was known in terms of its molecular biology. They made the remarkable finding that a mutation in a gene called BRAF switched on a signal pathway that drove cell proliferation in about two-thirds of melanomas. Remarkable because that gene had not previously been associated with any cancer. Even more amazingly, within a few years drugs had been developed that targeted BRAF and caused substantial regression of tumours that had spread (metastasized) in patients.

Like all cancers, melanoma is not caused by one mutation and other ‘drivers’ have since been identified – which was a bit of a relief because a perplexing thing about BRAF is that the mutation that turns it on is not the kind of genetic change caused by u.v. radiation. So the link between radiation, BRAF and melanoma is explained in most cases by u.v. exposure damaging a variety of genes which then act together with mutant BRAF to promote the disease.

Black, red & white mice

A different complexion

Clear so far? Good – but you will know that cricket and cancer have in common the fact that they are both a deal more complicated than they appear to the uninitiated. The first quirk of melanoma is that folk of fair complexion or with red hair or freckles are more at risk. The wide variation in human colouration is controlled by two forms of a pigment called melanin (pheomelanin and eumelanin). A key regulator of the balance between the two is a signalling system – a messenger talks to its receptor on the cell surface telling the cell to make more eumelanin. Upset this system and the balance is disturbed – you get redder because you make relatively more pheomelanin.

Mouse models

It’s possible to make a mouse model of human redheads (you shouldn’t be surprised: remember mice have more or less the same number of genes as us, including one that makes the receptor that controls redness). So some bright sparks in the US of A have done just that by mutating the mouse receptor – with interesting results. When the ‘red’ mice were bred with animals carrying the mutated BRAF gene associated with melanoma in humans, many develop exactly the same type of cancer – whereas black mice (lots of eumelanin) and white mice (who can make neither of the pigments) have very low rates of melanoma. And, of course, it was important in these experiments that the mice weren’t allowed to nip off to sunbathe and watch cricket – i.e. they were kept in a u.v.-free environment.

What this shows is that red mice (and by extension, their human counterparts) can get melanoma by some means that doesn’t involve u.v. It may be that eumelanin protects DNA from two forms of assault: it not only absorbs sunlight but also limits the effect of chemicals produced within the body that can mutilate our DNA.

Whatever the mechanism, Richie is right as usual: we should continue to Slip-Slop-Slap because too much catching the rays can cause melanoma – especially in fair, freckled red-heads. But that isn’t the full story and the imperfections of our bodies mean that we can develop this cancer from within as well as without.

Reference

Mitra, D., Luo, X., Morgan, A., Wang, J., Hoang, M.P. (2012). An ultraviolet-radiation-independent pathway to melanoma carcinogenesis in the red hair/fair skin background. Nature 491, 449–453.

http://www.nature.com/nature/journal/v491/n7424/full/nature11624.html

Pig’s ’ere – and far from a bore

First love

When I was a lad I quite often worked on my Uncle’s farm in Cumberland and it was there that I first fell in love. It was reciprocated too, in a sort of way – I think largely contingent on presenting myself regularly bearing armfuls of potato peelings and summoning the courage to lean over the wall and do a bit of ear tickling. To this day pigs remain a love of my life and, given my enthusiasm for the wonders of DNA sequencing, readers will be unsurprised that the convergence of the two is irresistible.

Sequencing Sus scrofa

The genome sequence of a female domestic pig (with the less than alluring name of T. J. Tabasco), together with those of some of her relatives, have just been published. Before we get on to why you less love-struck unfortunates should give a grunt, we should make clear that no animals were harmed in unveiling this sequence. Rather, a small piece of an ear or a few teaspoons of blood were enough to grow cells from which DNA was distributed to the research groups involved.

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Almost like a pig

So what did the members of the Swine Genome Sequencing Consortium gives us as the result of their labours? Well some things you would have guessed anyway: pigs have about as much DNA in their cells as we do (about 3,000 million base pairs). Of course they do: they’d have to be pretty similar for folk to go round falling in love with them. And within that sequence they have more genes encoding smell receptors than any other animal (over 1300) – which obviously helps if you have to rootle around for a bite to eat and not become reliant on admirers bringing gifts, though you can sense a downside to being so olfactorily endowed.

Them and us

But what about the differences? Well, close though I feel to them, pigs and humans last had a common ancestor about 90 million years ago and a domesticated pig first trotted out of South East Asia about 4 million years ago. Separate strains of the domestic pig then evolved in western Europe and East Asia that diverged from the various strains of wild boar – though the separation is somewhat murky due to pigs being prone to roam – a habit that led to what is delicately called ‘genetic mixing.’ So Hampshires and Large Whites turn out to be more closely related to European wild boars than they are to Chinese pigs such as the Meishan.

Model humans

One of the things that happened as pigs went their separate evolutionary way is that their DNA became unusually prone to being broken. Although damaged DNA is usually repaired two consequences tend to arise. Sometimes a gene just gets lost and this has happened with quite a few that we originally shared with pigs that enable us to taste things like salt: by losing that sensitivity pigs have acquired the ability to eat things we can’t. The other result is that pigs are quite good at shuffling bits of DNA to make novel genes (and hence proteins) – something called alternative splicing. But perhaps the most important outcome is that pig DNA has acquired about 100 changes (mutations) that in humans are linked to increased risk of things like Alzheimer’s disease and diabetes.

Pigs have a long and noble history as good models for human disease and we use their heart valves in replacement surgery (how’s that for reciprocated love?). Having a peek at their DNA has revealed that they also offer a natural model to find out what happens in some of our worst afflictions.

Pigs: giving us their hearts, sorting out our frailties – and making more roast dinners than you can shake a stick at. Everyone should love ‘em!

Reference

Groenen, M.A.M. et al., (2012). Analyses of pig genomes provide insight into porcine demography and evolution. Nature 491, 393-398.