A Musical Offering 

It’s generally accepted that Johann Sebastian Bach was one of the greatest, if not the greatest, musical composer of all time. In well over 1000 compositions he laid down the framework upon which rested virtually all Western music of the following 200 years. Of these works, The Musical Offering, written in 1747, is a collection of pieces based on a single theme that has been described as the most significant piano composition in history.

Along the way to becoming a unique composer, Bach married twice and sired twenty children, only ten of whom survived into adulthood. Those figures highlight another way in which JSB was something of a freak because, in 1750 when he died aged 65, the average life expectancy in Europe was under 40 years. For that reason cancers, being primarily being diseases of old age, were much less prominent then than now when, on average, we live to be over 80 and cancers account for about one in three deaths.

It’s safe to say that in the 18th century neither Bach nor anyone else knew anything of cancer yet alone that our genetic material carries tens of thousands of genes – a kind of molecular keyboard upon which cellular machinery plays to produce an output of proteins that distinguishes one cell type from another but is also continuously varying, even within individual cells. Bach would have been fascinated by this fluctuating molecular mosaic that, through the wonders of modern sequencing methods, we can display as ‘heat maps’ showing which genes are turned on (being expressed) and to what level.

Musical genes. Left: a heat map showing the pattern of genes being expressed at a given time in several different types of cell. Red: high expression level; green low expression. On the right is the same information transformed into musical notation using the Gene Expression Music Algorithm, GEMusicA (from Staege 2016).

With commendable vision a chap by the name of Martin Staege has come up with an alternative way of looking at the rather mind-blowing picture conveyed by heat maps. Staege is in the Martin Luther University of Halle-Wittenberg – appropriately as Bach’s eldest son studied at the University of Halle. His idea is that gene expression patterns can be transformed into sounds characterized by their frequency (pitch) and tone duration. In other words you can make genes play tunes – and what’s more compare the notes from different cell samples (e.g., normal and tumour cells) so that you can ‘hear’ the differences in gene expression.

Remarkable or what?!

Unsurprisingly, gene tunes sound more Alban Berg than Magic Flute, prompting the redoubtable Dr. Staege to go one step further by producing an algorithm that fits gene themes as best it can to more singable pieces – so you get a kind of difference melody. I don’t think Beethoven or Wagner would see this biological music as a threat and they might, like me, ask ‘what’s the point?’

To which, I guess, the answers are ‘It’s clever and fun’. It’s also yet another way of showing the power of DNA as an information storage medium, and making the point that in this guise it may, in due course, make a massive impact on our lives – much more mundane than musical genes but hugely more useful.

References

Staege, M. S. (2016). Gene Expression Music Algorithm-Based Characterization of the Ewing Sarcoma Stem Cell Signature. Stem Cells International
Volume 2016, Article ID 7674824, 10 pages http://dx.

Staege, M. S. (2015). A short treatise concerning a musical approach for the interpretation of gene expression data. Sci. Rep. 5, 15281.

 

 

 

 

 

 

Bigger is Better

“Nonsense!” most males would cry, quite logically, given that we spend much of our time trying to persuade the opposite sex that size doesn’t matter. But we want to have it both ways: in the macho world of rugby one of the oldest adages is that ‘a good big ’un will always beat a good little ’un’.  Beethoven doubtless had a view about size – albeit unrecorded by history – but after he’d written his Eroica symphony, perhaps the greatest revolutionary musical composition of all, his next offering in the genre was the magical Fourth – scored for the smallest orchestra used in any of his symphonies. And on the theme of small can be good, the British Medical Journal, no less, has just told us that if we cut the size of food portions and put ’em on smaller plates we’ll eat less and not get fat!

Is bigger better?

Is bigger better?

All of which suggests that whether bigger is better depends on what you have in mind. Needless to say, in these pages what we have in mind is ‘Does it apply to cancer?’ – that is, because cancers arise from the accumulation in cells of DNA damage (mutations), it would seem obvious that the bigger an animal (i.e. the more cells it has) and the longer it lives the more likely it will be to get cancer.

Obvious but, this being cancer, also wrong.

Peto’s Paradox

The first person to put his finger on this point was Sir Richard Peto, most famous for his work with Sir Richard Doll on cancer epidemiology. It was Doll, together with Austin Bradford Hill, who produced statistical proof (in the British Doctors’ Study published in 1956) that tobacco smoking increased the risk of lung cancer. Peto joined forces with Doll in 1971 and they went on to show that tobacco, infections and diet between them cause three quarters of all cancers.

Whenever this topic comes up I’m tempted to give a plug to the unfortunate Fritz Lickint – long forgotten German physician – who was actually the first to publish evidence that linked smoking and lung cancer and who coined the term ‘passive smoking’ – all some 30 years before the Doll study. Lickint’s findings were avidly taken up by the Nazi party as they promoted Draconian anti-smoking measures – presumably driven by the fact that their leader, Gröfaz (to use the derogatory acronym by which he became known in Germany as the war progressed – from Größter Feldherr aller ZeitenGreatest Field Commander of all Time) was a confirmed non-smoker. Despite his usefulness, Lickint’s political views didn’t fit the ideology of the times. He lost his job, was conscripted, survived the war as a medical orderly and only then was able to resume his life as a doctor – albeit never receiving the credit he deserved.

Returning to Richard Peto, it was he who in 1975 pointed out that across different species the incidence of cancer doesn’t appear to be linked to the number of cells in animal – i.e. its size.   He based his notion on the comparison of mice with men – we have about 1000 times the number of cells in a mouse and typically live 30 times as long. So we should be about a million times more likely to get cancer – but in fact cancer incidence is another of those things where we’re pretty similar to our little furry friends. That’s Peto’s Paradox.

It doesn’t seem to apply within members of the same species, a number of surveys having shown that cancer incidence increases with height both for men and women. The Women’s Health Initiative found that a four inch increase in height raised overall cancer risk by 13% although for some forms (kidney, rectum, thyroid and blood) the risk went up by about 25%. A later study found a similar association for ovarian cancer: women who are 5ft 6in tall have a 23% greater risk than those who only make it to 5 feet. A similar risk links ovarian cancer to obesity (i.e. a rise in body mass index from 20 (slim) to 30 (slightly overweight) puts the risk up by 23%). Statistically sound though these results appear to be, it’s worth nothing that, as my colleague Paul Pharoah has pointed out, these risk changes are small. For example, the ovarian cancer finding translates to a lifetime risk of about 16-in-a-1000 for shorter women going up to 20-in-a-1000 as they rise by 6 inches.

It’s true that there may be a contribution from larger animals having bigger cells (whale red blood cells are about twice as big as those of the mouse) that divide more slowly but at most that effect seems small and doesn’t fully account for the fact that across species the association of size and age with cancer breaks down: Peto’s Paradox rules – humans are much more likely to get cancer than whales.

What did we know?

Well, since Peto picked up the problem, almost nothing about underlying causes. The ‘almost’ has been confined to the very small end of the scale and we’ve already met the star of the show – the naked mole rat – a rather shy chap with a very long lifespan (up to 30 years) but who never seems to get cancer. In that piece we described the glimmerings of an explanation but, thanks to Xiao Tian and colleagues of the University of Rochester, New York we now know that these bald burrowers make an extraordinarily large version of a polysaccharide (a polymer of sugars). These long strings of glucose-like molecules (called hyaluronan) form part of the extracellular matrix and regulate cell proliferation and migration. They’re enormous molecules with tens of thousands of sugars linked together but the naked mole rat makes versions about four times larger than those of mice or humans – and it seems that these extra-large sugar strings restrict cell behaviour and block the development of tumours.

Going up!

Our ignorance has just been further lifted with two heavyweight studies, one from Lisa Abegglen, Joshua Schiffman and chums from the University of Utah School of Medicine who went to the zoo (San Diego Zoo, in fact) and looked at 36 different mammalian species, ranging in size from the striped grass mouse (weighing in at 50 grams) to the elephant – at 4,800 kilogram nearly 100,000 times larger. They found no relationship between body size and cancer incidence, a result that conforms to Peto’s paradox. Comparing cancer mortality rates it transpires that the figure for elephants is less than 5% compared with the human range of 11% to 25%.

107 final pic

Cancer incidence across species by body size and lifespan. A selection of 20 of the 36 species studied is shown. Sizes range from the striped grass mouse to the elephant. As the risk of cancer depends on both the number of cells in the body and the number of years over which those cells can accumulate mutations, cancer incidence is plotted as a function of size (i.e. mass in grams × life span, years: y axis: log scale). Each species is represented by at least 10 animals (from Abegglen et al., 2015).

It can be seen at a glance that cancer incidence is not associated with mass and life span.

The Tasmanian devil stands out as a remarkable example of susceptibility to cancer through its transmission by biting and licking.

How does Jumbo do it?

In a different approach to Peto’s Paradox, Michael Sulak, Vincent Lynch and colleagues at the University of Chicago looked mainly at elephants – more specifically they used DNA sequencing to get at how the largest extant land mammal manages to be super-resistant to cancer. In particular they focused on the tumor suppressor gene P53 (aka TP53) because its expression is exquisitely sensitive to DNA damage and when it’s switched on the actions of the P53 protein buy time for the cell to repair the damage or, failing that, bring about the death of the cell. That’s as good an anti-cancer defence as you can imagine – hence P53’s appellation as the ‘guardian of the genome’. It turned out that elephants have no fewer than 20 copies of P53 in their genome, whereas humans and other mammals have only one (i.e. one copy per set of (23) chromosomes). DNA from frozen mammoths had 14 copies of P53 but manatees and the small furry hyraxes, the elephant’s closest living relatives, like humans have only one.

The Utah group confirmed that elephants have, in addition to one normal P53 gene, 19 extra P53 genes (they’re actually retrogenes – one type of the pseudogenes that we met in the preceding post) that have been acquired as the animals have expanded in size during evolution. Several of these extra versions of P53 were shown to be switched on (transcribed) and translated into proteins.

Consistent with their extra P53 fire-power, elephant cells committed P53-dependent suicide (programmed cell death, aka apoptosis) more frequently than human cells when exposed to DNA-damaging radiation. This suggests that elephant cells are rather better than human cells when it comes to killing themselves to avoid the risk of uncontrolled growth arising from defective DNA.

More genes anyone?

Those keen on jumping on technological bandwagons may wish to sign up for an extra P53 gene or two, courtesy of genetic engineering, so that bingo! – they’ll be free of cancers. Aside from the elephant, they may be encouraged by ‘super P53’ mice that were genetically altered to express one extra version of P53 that indeed significantly protected from cancer when compared with normal mice – and did so without any evident ill-effects.

We do not wish to dampen your enthusiasm but would be in dereliction of our duty is we did not add a serious health warning. We now know a lot about P53 – for example, that the P53 gene encodes at least 15 different proteins (isoforms), some of which do indeed protect against cancer – but there are some that appear to act as tumour promoters. In other words we know enough about P53 to realize that we simply haven’t a clue. So we really would be playing with fire if we started tinkering with our P53 gene complement – and to emphasise practicalities, as Mel Greaves has put it, we just don’t know how well the elephants’ defences would stack up if they smoked.

Nevertheless, on the bright side, light is at long last beginning to be shed on Peto’s Paradox and who knows where that will eventually lead us. Meanwhile Richard Peto’s activities have evolved in a different direction and he now helps to run a Thai restaurant in Oxford, a cuisine known for small things that pack a prodigious punch. Bit like Beethoven’s Fourth you could say.

a-gem-of-a-find-in-oxford

References

Peto, R. et al. (1975). Cancer and ageing in mice and men. British Journal of Cancer 32, 411-426.

Doll, R. and Peto, R. (1976). Mortality in relation to smoking: 20 years’ observations on male British doctors. Br Med J. 2(6051):1525–36.

Maciak, S. and Michalak, P. (2015). “Cell size and cancer: A new solution to Peto’s paradox?”. Evolutionary Applications 8: 2.

Doll, R. and Hill, A.B. (1954). “The mortality of doctors in relation to their smoking habits”. BMJ 328 (7455): 1529.

Doll, R. and Hill, A.B. (November 1956). “Lung cancer and other causes of death in relation to smoking; a second report on the mortality of British doctors”. British Medical Journal 2 (5001): 1071–1081.

Tian, X. et al. (2013). High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature 499, 346-349.

Abegglen, L.M., Schiffman, J.D. et al. (2015). Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans. JAMA. doi:10.1001/jama.2015.13134.

Sulak, M., Lindsey Fong, Katelyn Mika, Sravanthi Chigurupati, Lisa Yon, Nigel P. Mongan, Richard D. Emes, Vincent J. Lynch, V.J. (2015). TP53 copy number expansion correlates with the evolution of increased body size and an enhanced DNA damage response in elephants. doi: http://dx.doi.org/10.1101/028522.

García-Cao, I. et al. (2002). ‘Super p53’ mice exhibit enhanced DNA damage response, are tumor resistant and age normally. EMBO Journal 21, 6225–6235.

Twists in a Tale: The trials, tribulations and unexpected treats that accompanied the writing of Betrayed by Nature

An old adage holds that everyone has a novel in them. It’s readily exploded, of course, by a glance at the widespread levels of illiteracy revealed by Twitter and other contemporary organs of unfettered soul-pouring. “No it isn’t” you retort, having glanced at one or two books that have done rather well of late. A fair point. Maybe it’s all these ‘writing seminars’ and ‘how to write a book’ books – everyone knows it’s dead easy to become a proper author: précis the plot, write out a detailed plan, discuss it with your publisher (all signed up and ready to go) and devise a rigid schedule: rise at five, 3,000 words by lunchtime, two hours kip, another 2,000 words, dinner, bed, reprise next day until finished. Finally, select the exotic location to which you will retire on the proceeds.

Once upon a time I sat down to write a novel. It was about cancer – not yet another of those estimable but rather egocentric and uninformative accounts of ‘battling against the odds’ but rather a sci-nov – a book that reads like a novel but where science (and the folk that do it) make the story. In ‘sci-nov’ I may have invented an acronym but certainly not a new genre. Writing science as a story is to walk in footsteps that have borne the brilliance of Steve Jones and Matt Ridley to mention only two luminaries – so you experience full well the trepidation that assailed Brahms in trying to write symphonies after Beethoven had a bit of a crack at it.

How not to write a book

But nowadays if you fancy trying it you know exactly what to do. Follow the above instructions and Bob’s your uncle. Except I didn’t. Do any of that. I just told myself someone should write this story – so get on with it. And I started with the first thing that occurred to me as dimly relevant. But after, I suppose, a couple of sentences I hit a problem. Proper authors reading this are doubtless smirking “Bit early to get writer’s block” but it wasn’t that.

For me the problem is called being a scientist. It simply is an utter pain having ingrained into you the notion that there are facts and that where facts are known you should jolly well get them right, as well as making them contribute to a clear and fascinating story. Oh to be scratching away at chick-lit or similar drivel! So by dinner-time on day one we had the grand total of 39 words. We’d spent hours trying to discover the birthday of William Norris (he was the first to spot that cancers might be heritable), judging the fairness of describing Jim Watson (the DNA double helix chap) as untidy and in deciding whether to note the annual number of cancer deaths in the world as 7½ million, 7.5 million, 7,564,802 or just round it up to eight million (thank you World Health Organization).

If someone had told me I’d got lucky that morning I would, of course, have given up – but it did indeed transpire, seven years and 100,000 words later, that on Day One I’d managed what was to become, almost exactly, my average daily rate.

But no one was there to utter such dire prophesies and so, one May day in New York in 2012, I found myself autographing my first fly-leaf dedication. Astonishing? I’ll say – sci-nov becomes sci-fi – but, remarkable to relate, this wasn’t my first amazing ‘author’ experience. Several months earlier I was beginning to grasp that popular science is a different world – a parallel universe to that of ‘normal’ science. Where I normally live, once something’s published it pretty well disappears into the facts mountain and you get on with the next experiment. In the ‘pop’ world you have to publicise – or to put it more painfully – self-publicise.

The first intimations of this came in a brief lecture from youngest son: “If you think it’s worth writing you must make an effort to tell everyone about it. You need a blog, Squire.” A quick visit to Wikipedia revealed that he was talking about a web log – a discussion or information site. But what to ‘discuss’ or ‘inform’ about? All I wanted to say was ‘read the book (subliminal message: it’s terrific).’ Re-consulting the Son Oracle elicited the instruction that “You need to pick up current cancer stories and explain them simply and clearly – that is, do it better than the science journalists. Should be a doddle for you. Let me have a look at your first effort and I’ll tell you if you’re on the right lines.” Gee one’s nearest and dearest can be so annoying!

Son Oracle has a word with Charles Darwin about the descent of man

That was how I met Susan. Our courtship was a paradigm of our times, conducted most chastely through the medium invented by Sir TimBL. She was looking for distraction, not in the usual sort of way, I hasten to add, but from embarking on post-surgical chemotherapy for bowel cancer. As a virgin blogger I was just desperate for someone experienced to tell me what to do. In the traditional male fashion my overtures were very much of the hope rather than anticipation variety – even with my manic enthusiasm for cells and molecules I had to admit that someone grappling with colorectal carcinoma might find less than irresistible the post of Reviewing Editor (unpaid) for articles on cancer. But no! She said yes!! Aren’t women amazing?!!! And this one stuck to her word by marking my first essay – with disconcerting perception – within 24 hours (university tutors please note!). And so our secret affair has blossomed and in the process we have become, as in the best of relationships, the best of friends.

I know, it’s a tear-jerker – but try this for a twist. Coincidentally with the book coming out – almost to the day – Susan had a meeting with her oncologist after which she vividly described the moment when he said what must to her have been almost unbelievable words:“Congratulations. You appear to be in full remission.”

All that before becoming a sci-nov author – clearly life after birth was going to be one long anti-climax. Well, that’s not exactly how it’s shaping up. I’d scarcely staggered from the literary delivery room when I was asked to talk at a meeting organised by Peterborough NHS – really to tell people about cancer. I found myself sharing the platform with a lovely lady called Jean who, after I’d warbled on about DNA and cells and coerced the audience into performing a bit of molecular theatre, told them what it had been like to find she had cancer. She used her experience to explain the tell-tale signs of the major cancers and then talked very simply and clearly about how she had dealt with all the ensuing stress arising from her particular version. Witnessing her courage in re-living difficult times for the benefit of others was quite an experience. I’m not sure how much attention they paid to me and molecules, but when Jean was speaking a falling pin would have been a serious distraction.

How did that happen then?

Meeting these wonderful people was not on the menu when I sat down to write Betrayed by Nature. There were three simple aims: write something enjoyable to read, get people interested in biology, and help folk deal with cancer. It never crossed my mind that becoming an author could confer the privilege of meeting Susan and Jean. I don’t know how successful the book will be but if it has a fraction of the effect that they have on those who hear their stories, no exotic retirement spot could offer equal contentment.