Be amazed


Back in May 2018 we reported the first output from the Pan-Cancer Atlas, a massive undertaking that evolved from The Cancer Genome Atlas, itself a huge project aiming to set up a genetic data-base for three cancer types: lung, ovarian, and glioblastoma.

The next instalment from the Pan-Cancer Analysis of Whole Genomes (PCAWG) has just appeared featuring the analysis of a staggering 2,658 whole-cancer genomes and their matching, normal tissues across 38 tumour types and it has reminded us, yet again, of nature’s capacity to surprise. The first finding was that, on average, cancer genomes contained four or five driver mutations when coding and non-coding genomic elements were combined. That’s roughly consistent with the accepted estimate over the last few decades. What was unexpected, however, was that in around 5% of cases no drivers were identified, suggesting that there are more of these mutations to be discovered. Also somewhat surprising is that chromothripsis, the single catastrophic event producing simultaneously many variants in DNA, is frequently an early event in tumour evolution.

The analyses also revealed several mechanisms by which the ends of chromosomes in cancer cells are protected from telomere attrition and that variants transmitted in the germline can affect subsequently acquired patterns of somatic mutation.

A glimpse of the data

The panorama of driver mutations includes the summary below of tumour-suppressor genes with biallelic inactivation (i.e., mutation of one allele (copy) followed by gene deletion of the remaining allele) in 10 or more patients. Familiar tumour suppressors are prominent on the left hand side, as expected. These include TP53 (the guardian of the genome) and the tumour suppressors CDKN2A and CDKN2B (cyclin-dependent kinase inhibitors 2A and 2B) that regulate the cell cycle.

Tumour-suppressor genes for which both copies of the gene (alleles) are inactivated in 10 or more patients. GR = genomic rearrangement, i.e. chromosome breakage. From The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium.

Aneuploidy in the genome of a tumour without known drivers. Each row is an individual tumour: the boxes show chromosome loss (blue) or gain (red). The cancer is a rare kidney tumour (chromophobe renal cell carcinoma). From The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium.

Two tumour types had a surprisingly high fraction of patients without identified driver mutations: 44% for a rare type of kidney cancer (chromophobe renal cell carcinoma) and 22% in a rare pancreatic neuroendocrine cancer. It turned out (as shown in the above figure) that there was a striking loss or gain of chromosomes — called aneuploidy — in the cells of these cancers. This suggests that wholesale loss of tumour suppressor genes or gain of oncogenic function was providing the ‘drivers’ for these cancers.

The genomic cancer message

We should first acknowledge the mind-boggling effort and organization involved in collecting thousands of paired samples, sequencing them and analyzing the output. However, the value of these massive projects is beginning to emerge — and the news is mixed.

One critical trend is that genomic analysis is re-defining the way cancers are classified. Traditionally they have been grouped on the basis of the tissue of origin (breast, bowel, etc.) but this will gradually be replaced by genetic grouping, reflecting the fact that seemingly unrelated cancers can be driven by common pathways.

Perhaps the most encouraging thing to come out of the genetic changes driving these tumours is that for about half of them potential treatments are already available. That’s quite a surprise but it doesn’t mean that hitting those targets will actually work as anti-cancer strategies. Nevertheless, it’s a cheering point that the output of this phenomenal project may, as one of the papers noted, serve as a launching pad for real benefit in the not too distant future.

On the other hand, the intention of precision medicine is to match patients to therapies on the basis of genomics and, notwithstanding the above point, the consortium notes that “A major barrier to evidence-based implementation is the daunting heterogeneity of cancer chronicled in these papers, from tumour type to tumour type, from patient to patient, from clone to clone and from cell to cell. Building meaningful clinical predictors from genomic data can be achieved, but will require knowledge banks comprising tens of thousands of patients with comprehensive clinical characterization. As these sample sizes will be too large for any single funding agency, pharmaceutical company or health system, international collaboration and data sharing will be required.”

See for yourself

The PCAWG landing page ( provides links to several data resources for interactive online browsing, analysis and download of PCAWG data.


The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis of whole genomes.


Non-Container Ships


A question often asked about cancer is: “Can you catch it from someone else?” Answer: “No you can’t.” But as so often in cancer the true picture requires a more detailed response — something that may make scientists unpopular but it’s not our fault! As Einstein more or less said “make it as simple as possible but no simpler.”

No … but …

So we have to note that some human cancers arise from infection — most notably by human immunodeficiency viruses (HIV) that can cause acquired immunodeficiency syndrome (AIDS) and lead to cancer and by human papillomavirus infection (HPV) that can give rise to lesions that are the precursors of cervical cancer. But in these human cases it is a causative agent (i.e. virus) that is transmitted, not tumour cells.

However, there are three known examples in mammals of transmissible cancers in which tumour cells are spread between individuals: the facial tumours that afflict Tasmanian devils, a venereal tumour in dogs and a sarcoma in Syrian hamsters.

Not to be outdone, the invertebrates have recently joined this select club and we caught up with this extraordinary story in Cockles and Mussels, Alive, Alive-O! It’s a tale of clams and mussels and various other members of the huge family of bivalve molluscs — (over 15,000 species) — that began 50 years ago when some, living along the east and west coasts of North America and the west coast of Ireland, started to die in large numbers. It turned out that the cause was a type of cancer in which some blood cells reproduce in an uncontrolled way. It’s a form of leukemia: the blood turns milky and the animals die, in effect, from asphyxiation. In soft-shell clams the disease had spread over 1,500 km from Chesapeake Bay to Prince Edward Island but the really staggering fact came from applying the power of DNA sequencing to these little beach dwellers. Like all cancers the cause was genetic damage — in this case the insertion of a chunk of extra DNA into the clam genome. But amazingly this event had only happened once: the cancer had spread from a single ‘founder’ clam throughout the population. The resemblance to the way the cancer spreads in Tasmanian devils is striking.

Join the club

In 2016 four more examples of transmissible cancer in bivalves were discovered — in mussels from British Columbia, in golden carpet shell clams from the Spanish coast and in two forms in cockles. As with the soft-shell clams, DNA analysis showed that the disease had been transmitted by living cancer cells, descended from a single common ancestor, passing directly from one animal to another. In a truly remarkable twist it emerged that cancer cells in golden carpet shell clams come from a different species — the pullet shell clam — a species that, by and large, doesn’t get cancer. So they seem to have come up with a way of resisting a cancer that arose in them, whilst at the same time being able to pass live tumour cells on to another species!!

Map of the spread of cancer in mussels. This afflicts the Mytilus group of bivalve molluscs (i.e. they have a shell of two, hinged parts). BTN = bivalve transmissible neoplasias (i.e. cancers). BTN 1 & BTN2 indicates that two separate genetics events have occurred, each causing a similar leukemia. The species involved are Mytilus trossulus (the bay mussel), Mytilus chilensis (the Chilean blue mussel) and Mytilus edulis (the edible blue mussel). The map shows how cancer cells have spread from Northern to Southern Hemispheres and across the Atlantic Ocean. From Yonemitsu et al. (2019).

Going global

In the latest instalment Marisa Yonemitsu, Michael Metzger and colleagues have looked at two other species of mussel, one found in South America, the other in Europe. DNA analysis showed that the cancers in the South American and European mussels were almost genetically identical and that they came from a single, Northern hemisphere trossulus mussel. However, this cancer lineage is different from the one previously identified in mussels on the southern coast of British Columbia.

Unhappy holidays

It seems very likely that some of these gastronomic delights have hitched a ride on vessels plying the high seas so that carriers of the cancer have travelled the oceans. Whilst one would not wish to deny them the chance of a holiday, this is serious news because of the commercial value of seafood.

It’s another example of how mankind’s advances, in this case being able to build things like container ships with attractive bottoms, for molluscs at least, can lead to unforeseen problems.

This really bizarre story has only come light because of the depletion of populations of clams and mussels in certain areas but it certainly carries the implication that transmissible cancers may be relatively common in marine invertebrates.


Yonemitsu, M.A. et al. (2019). A single clonal lineage of transmissible cancer identified in two marine mussel species in South America and Europe. eLife 2019;8:e47788 DOI: 10.7554/eLife.47788.

Guess Who’s Coming to Dinner?


Question: when is a gene not a gene? Answer: when it’s a pseudogene.

Genes are familiar enough these days when the acronym DNA has become part of everyday speech “It is in Toyota’s DNA that mistakes made once will not be repeated”, as the CEO of Toyota rather sinisterly remarked. You could say that’s pseudo-scientific rubbish but, despite that kind of liberty-taking, most will know that a gene is a stretch of our genetic material (DNA) that carries the code to make a closely related RNA molecule that, in turn, may be used as a template to make a protein ­– it’s the molecular unit of heredity. Well known too is that the Greeks gave us ‘pseudo’ – but what’s a ‘lying’ or ‘false’ gene – and who cares?

No prizes for guessing that we should all be interested because it’s emerging that pseudogenes can be important players in cancer.

Player’s biography

Pseudogenes are somewhat disreputable because they are relatives of normal genes that along the evolutionary highway have become dysfunctional by losing the capacity to be ‘expressed’ – that is, their code can no longer be transformed into RNA and protein. You could think of them as an example of the shambolic way in which species have evolved by random happenstance so that they work in their own particular niches. And if you want the outstanding example of unintelligent design, look no further than yourself, as we did in Holiday Reading (2), Poking the Blancmange.

Just for background, although it doesn’t affect the main story, there are three ways in which our genome can acquire a pseudogene:

1. A normal gene becomes functionally extinct: odd mutational events disable the stretches of DNA that control its expression. The gene is like a siding on a railway that isn’t used for years and years until eventually the points  seize up (it would be a ‘switch’ on US railroads) and the cell machinery can no longer get at it – but when this does happen we get by without that gene.

2. During evolution genes quite often get duplicated – giving multiple copies: if one of these loses its regulatory bits the duplicate gene is switched off – it’s become a ghost.

3. We owe about 8% of our genome to viruses – mainly those with RNA genomes (retroviruses) whose life-cycle turns their RNA into DNA that has then been stuck into our genome. And that’s a lot (about 100,000 bits of retrovirus DNA) especially bearing in mind that only about 1% of our genome encodes proteins.

So our precious genome is littered with corpses and fragments thereof. In the past there’s been a regrettable tendency to label this material as ‘junk’ but increasingly we’re now discovering that there may be genetic life after death, so to speak. It’s not surprising if you think about it. If random events can inactivate a gene then they might do the reverse, even if that may be a much rarer event. And indeed it’s now clear that pseudogenes can be brought back to life through the random mutational events that characterise the rough and tumble of cellular life.

So not all pseudogenes are extinct then?

Correct. Obviously we wouldn’t be wittering on about them had not some bright sparks just shown that pseudogenes – or at least one in particular – can be re-awakened to play a part in cancer. The luminaries are Florian Karreth, Pier Paolo Pandolfi and friends from all over the place (USA, UK, Italy, Singapore) who found that a pseudogene called BRAFP1 (a relative of the normal BRAF gene) can help to drive cancer development. Some earlier studies had shown that BRAFP1 was expressed (i.e. RNA was made from DNA) in various human tumours but Karreth & Co extended this, detecting significant levels of the pseudogene RNA in lymphomas and thyroid tumours and also in cells from melanoma, prostate cancer and lung cancer, whilst it’s not switched on in the corresponding normal cells.

To show that this pseudogene can drive cancers they genetically engineered its over-expression in mice, whereupon the animals developed an aggressive malignancy akin to human lymphoma (specifically diffuse large B cell lymphoma). Short-circuiting an enormous amount of work, it emerged that the pseudogene up-regulated a signaling pathway involving its normal counterpart, BRAF, that drives proliferation.

106 pic

How a pseudogene (BRAFP1) might drive cancer. Top: The scheme illustrates the ‘central dogma’ of molecular biology: DNA makes RNA makes protein. In normal cells a family of micro RNAs (different coloured wiggles) regulate the level of BRAF RNA and hence of BRAF protein (above white line).  Bottom: When the pseudogene BRAFP1 is switched on its RNA competes for the negative regulators: the result is more BRAF RNA making more BRAF protein – making cancer (Karreth et al., 2015).

Interfering RNA

The pseudogene’s RNA manages to interfere with normal control by targeting another type of RNA – micro RNAs, so called because they’re very short (about 20 bases (units) long – so they’re encoded by tiny stretches of the over 3,000 million units that make up the genome). Small they may be but there are hundreds of them and it’s become clear over the last few years that they play critical roles in regulating how much protein is made from specific RNAs. Their method is simple: they recognize (i.e. bind to) stretches of RNA that encode proteins, thereby blocking translation into protein.

Karreth & Co showed that there are about 40 different micro RNAs that can stick to the RNAs encoding BRAF or BRAFP1. Normally when there’s no (or very little) BRAFP1 around they have only BRAF to act on – and their role is to control the proliferation signal it transmits – i.e. to keep that signal to what’s required for normal cell growth control. BUT, when the pseudogene RNA is made in significant amounts the attentions of the 40 micro RNAs are divided. Result: more BRAF RNA, more BRAF protein, higher cell proliferation.

It’s a bit like you’re just sitting down to a family dinner for four when there’s a knock on the door and in walks long lost Uncle Bert, complete with wife and two kids in tow. Of course you invite them to dine too – but now a meal for four has to stretch to eight. There is something for everybody – just not as much. Similarly for the regulators of BRAF: when BRAFP1 is present there’s half as much of the RNA regulators for each – and the result, bearing mind that they are negative regulators, is that the activity of BRAF goes up and the cells proliferate more avidly. The pseudogene is driving cancer.

First but not last

For decades pseudogenes were thought of as ‘junk’ DNA along with most of the rest of the genome that didn’t encode proteins – though I might say that was a concept I never promoted. Beware labeling anything in our genome as junk for it may rise, Kraken like, to remind us of our ignorance. And, now that one pseudogene has come in from the cold and been shown to drive some cancers, you can be confident that others will follow.


Karreth, F.A. et al. (2015). The BRAF Pseudogene Functions as a Competitive Endogenous RNA and Induces Lymphoma In Vivo. Cell 161, 319–332.

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.

Not getting cancer: a sequel to sequencing and evolution

The previous Kamilah the gorilla story leads us – where else – to the Naked Mole Rat. Addicted Naturists will have read last year that it too had been sequenced. Why on earth would they want the DNA code of the NMR? Maybe part of some fiendish chimeric cloning experiment inspired by The Wind in the Willows – these boffins need to get out more. But wait a minute! Despite the advances that mean genomes can be sequenced in a day, it’s still a complicated and expensive business – so there has to be a good reason for tackling another strain or species, as we saw with the gorillas. But what might that be for the humble NMR?

Water vole

Naked mole rat

It turns out that NMRs are far more astonishing chaps than even Kenneth Grahame could have imagined. In a way they’re rather well-named, being neither mole nor rat but a distinct species that diverged from rats and mice about 70 million years ago – much as the water vole (aka ‘Ratty’) is only distantly related to a true rat – and it parted company from us 20 million years earlier still. It’s a burrowing rodent so has to get by on low levels of oxygen, which it manages by having very small lungs and haemoglobin that is unusually efficient at picking up oxygen. When times get tough it can reduce its metabolic rate to a quarter of normal, its body temperature follows that of its surroundings, it doesn’t feel pain because its skin doesn’t make the required neurotransmitter, it lives in communes with a queen (the only one to reproduce – like some ants and bees) and it’s the longest-living rodent (over 30 years).

How amazing is that for a set of party pieces? But these stunning little tunnelers have one other trick that puts everything else in the shade. NMRs don’t get cancer. At least tumours have never been found in these fellers and if you take some of their cells, make them express a cancer-promoting gene and put them back into animals they still don’t form tumours – even though you get very aggressive growths if you do the same thing with mouse or rat cells.

What’s the secret of Naked Rats not getting cancer?

So what has the full DNA sequence of the NMR told us? Two genes have come to the fore that are very slightly altered compared with their human counterparts, and they’re of particular interest because we know they play major roles in protecting us – to the extent that they are knocked out in the majority of human cancers. What’s different in the NMR? Perhaps surprisingly, their variant genes make proteins that are just a little bit smaller than the human versions. Surprising because intuitively you might think that bigger would be better. However, proteins are almost incomprehensibly subtle creations – recall that changing just one amino acid out of 1480 in a protein made in the lung is enough to cause cystic fibrosis – and it may be that the slight changes in the DNA code do just enough to the shape of these proteins to make them ‘super’ protectors. The next step is to see what the NMR proteins do when they’re expressed in transgenic mice.

None of this means that the NMR is going to save mankind from one of its greatest scourges but it is encouraging that it has focussed attention on some of the key genes that stop us getting cancer. The other upshot is that it has reminded us how extraordinarily delicate is the balance in living things and how the slightest of changes in a protein can have immense effects.


Kim, E.B. et al. (2011). Genome sequencing reveals insights into physiology and longevity of the naked mole rat. Nature 479, 223–227.