Making Movies in DNA

Last time we reminded ourselves of one of the ways in which cancer is odd but, of course, underpinning not just cancers but all the peculiarities of life is DNA. The enduring wonder is how something so basically simple – just four slightly different chemical groups (OK, they are bases!) – can form the genetic material (the instruction book, if you like) for all life on earth. The answer, as almost everyone knows these days, is that there’s an awful lot of it in every cell – meaning that the four bases (A, C, G & T) have an essentially infinite coding capacity.

That doesn’t make it any the less wonderful but it does carry a huge implication: if something you can squeeze into a single cell can carry limitless information it must be the most powerful of all storage systems.

A picture’s worth a thousand words

We looked at the storage power of DNA a few months ago (in “How Does DNA Do It?”) and noted that its storage density is 1000 times that of flash memories, that it’s fairly easy to scan text and transform the pixels into genetic code and that, as an example, someone has already put Shakespeare’s sonnets into DNA form.

Now Seth Shipman, George Church and colleagues at Harvard have taken the field several steps forward by capturing black and white images and a short movie in DNA. Moreover they’ve managed to get these ‘DNA recordings’ taken up by living cells from which they could subsequently recover the images.

Crumbs! How did they do it?

First they used essentially the text method to encode images of a human hand: assign the four bases (A, C, G & T) to four pixel colours (this gives a grayscale image: colours can be acquired by using groups of bases for each pixel). These DNA sequences were then introduced into bacteria (specifically E. coli) by electroporation (an electrical pulse briefly opens pores in the cell membrane).

The cells treat this foreign DNA as though it was from an invading virus and switch on their CRISPR system (summarized in “Re-writing the Manual of Life”). This takes short pieces of viral DNA and inserts them into the cell’s own genome in the form of ‘spacers’ (the point being that the stored sequences confer ‘adaptive immunity’: the cell has an immunological memory so it is primed to respond effectively if it’s infected again by that viral pathogen).

In this case, however, the cells have been fooled: the ‘spacers’ generated carry encoded pictures, rather than viral signatures.

Because spacers are short it’s obvious that you’ll need lots of them to carry the information in a photo. To keep track when it comes to reassembling the picture, each DNA fragment was tagged with a barcode (and fortunately we explained cellular barcoding in “A Word From The Nerds”).

Once incorporated in the bugs the information was maintained over many bacterial generations (48 in fact) and is recoverable by high-throughput sequencing and reconstruction of the patterns using the barcodes.

And the movie bit?

Simple. In principle they used the same methods to encode sequential frames.

Pictures in DNA.

Top: Using triplets of bases to encode 21 pixel colours. Images of a human hand (top) and a horse (bottom) were captured. For the movie they used freeze frames taken in 1872 by the English photographer Eadweard Muybridge. These showed that, for a fraction of a second, a galloping horse lifts all four hooves off the ground. Seemingly this won a return for the sometime California governor, Leland Stanford (he of university-founding fame) who had put a wager on geegees doing just that. From Shipman et al., 2017. You can see the movie here.

Getting the picture clear

To recap, in case you’re wondering if this is some scientific April Fools’ prank. What Church & Co. did is scan pictures and transform pixel density into the genetic code (i.e. sequences of the four bases A, C, G & T). They then made DNA carrying these sequences, persuaded bacteria to take up the DNA and incorporate it into their own genomes and, after growing many generations of the bugs, extracted their DNA, sequenced it and reconstructed the original images. By scanning sequential frames this can be extended to movies.

It’s not science fiction – but it is pretty amazing. With a droll turn of phrase Seth Shipman said “We want to turn cells into historians” and the work does have significant implications in showing something of the scope of biological memory systems.

Won’t be long before the trendy, instead of birthday presents of electronic family photo albums, are giving small tubes of bugs!


Shipman, S.L., Nivala, J., Macklis, J.D. & Church, G.M. (2017). CRISPR–Cas encoding of a digital movie into the genomes of a population of living bacteria. Nature 547, 345–349.


Cancer GPS?

The thing that pretty well everyone knows about cancers is that most are furtive little blighters. They kill one in three of us but usually we don’t they’re there until they are big enough to make something go wrong in the body or to show up in our seriously inadequate screening methods. In that sense they resemble heart problems of one sort or another, where often the first indication of trouble is unexpectedly finding yourself lying on the floor.

Meanwhile, out on the highways and byways you are about 75 times less likely to be killed in an accident than you are to succumb to either cancers or circulation failure. Which is a way of saying that in the UK about 2000 of us perish on the roads each year. That it’s ‘only’ 2000 is presumably because here your assailant is anything but furtive. All you’ve got to do is side-step the juggernaut and you’ll probably live to be – well, old enough to get cancer.

Did you know, by the way, that ‘juggernaut’ is said to come from the chariots of the Jagannath Temple in Puri on the east coast of India. These are vast contraptions used to carry representations of Hindu gods on annual festival days that look as though walking pace would be too much for them. So, replace the monsters on our roads with real juggernauts! Problem largely solved!!

Flagging cancer

But to get back to cancer or, more precisely, the difficulty of seeing it. After centuries of failing to make any inroads, recent dramatic advances give hope that all is about to change. These rely on the fact that tissues shed cells – and with them DNA – into the circulation. Tumours do this too – so in effect they are scattering clues to their existence into blood. By using short stretches of artificial DNA as bait, it’s possible to fish out tumour cell DNA from a few drops of 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 other cells in every cubic millimeter of blood.

There are two big attractions in this ‘microfluidics’ approach. First it’s almost ‘non-invasive’ in needing only a small blood sample and, second, it is possible that indicators may be picked up long before a tumour would otherwise show up. In effect it’s taking a biochemical magnifying glass to our body to ask if there’s anything there that wouldn’t normally be present. Detect a marker and you know there’s a tumour somewhere in the body, and if the marker changes in concentration in response to a treatment, you have a monitor for how well that treatment is doing. So far, so good.

And the problem?

These ‘liquid biopsy’ methods that use just a teaspoonful of blood have been under development for several years but there has been one big cloud hanging over them. They appear to be exquisitely sensitive in detecting the presence of a cancer – by sequencing the DNA picked up – but they have not been able to pinpoint the tissue of origin. Until now.

Step forward epigenetics

Shuli Kang and colleagues at the University of California at Los Angeles and the University of Southern California have broken this impasse by turning to epigenetics. We noted in Twenty More Winks that an epigenetic modification is any change in DNA, other than in the sequence of bases (i.e. mutation), that affects how an organism develops or functions. They’re brought about by tacking small chemical groups (commonly methyl (CH3) groups) either on to some of the bases in DNA itself or on to the proteins (histones) that act like cotton reels around which DNA wraps itself. The upshot is small changes in the structure of DNA that affect gene expression. You can think of DNA methylation as a series of flags dotted along the DNA strand, decorating it in a seemingly random pattern. It isn’t random, of course, and the target for methylation is a cytosine nucleotide (C) followed by a guanine (G) in the linear DNA sequence – called a CpG site because G and C are separated by one phosphate (p). Phosphate links nucleosides together in the backbone of DNA.

Cancer cells often display abnormal DNA methylation patterns – excess methylation (hypermethylation) in some regions, reduced methylation in others – that contributes to their peculiar behavior. It’s possible to determine the methylation profile of a DNA sample (by a method called bisulfite sequencing).

Kang & Co. developed a computer program to analyse methylation profiles from solid tumours and healthy samples in public databases and compare them to patient DNA of unknown tissue origin.

The peaks represent CpG clusters that characterize normal cells (top) and a variety of cancers. The key point is that the different patterns identify the tissue of origin (from Kang, S. et al., 2017).

The program’s called CancerLocator and in this initial study it was used to test samples from patients with lung, liver or breast cancer. In the modest words of the authors, CancerLocator ‘vastly outperforms’ previous methods – mind you, they struggle to even to distinguish most cancer samples from non-cancer samples. Nevertheless, CancerLocator’s a big step forward, not least because it can detect early stage cancers with 80% accuracy.

It’s also reasonable to expect major improvements as methylation sequencing becomes more extensive and higher resolution reveals more subtle signatures. What’s more, in principle, it should be able to detect all types of cancers – meaning that, after all so many centuries we may at last have a way of side-stepping the juggernaut.


Kang, S. et al. (2017). CancerLocator: non-invasive cancer diagnosis and tissue-of-origin prediction using methylation profiles of cell-free DNA. Genome Biology DOI 10.1186/s13059-017-1191-5.

And Now There Are Six!!

Scientists eh! What a drag they can be! Forever coming up with new things that the rest of us have to wrap our minds around (or at least feel we should try).

Readers of these pages will know I’m periodically apt to wax rhapsodic about ‘the secret of life’ – the fact that all living things arise from just four different chemical units, A, C, G and T. Well, from now on it seems I’ll need to watch my words – or at least my letters – though maybe for a while I can leave it on the back burner in the “things that have been but not yet” category, to use the melodic prose of Christopher Fry.

Who dunnit?

The problem is down to Floyd Romesberg and his team at the Scripps Research Institute in California.

Building on a lot of earlier work, they’ve made synthetic units that stick together to form pairs – just like A-T and C-G do in double-stranded DNA. But, as these novel chemicals (X & Y) are made in the lab, the bond they form is an unnatural base pair.

Left: Two intertwined strands of DNA are held together in part by hydrogen bonds. Right top: Two such bonds (dotted lines) link adenine (A) to thymine (T); three form between guanine (G) and cytosine (C). These bases attach to sugar units (ribose) and phosphate groups (P) to form DNA chains. Right bottom: Synthetic X and Y units can also stick together and, via ribose and phosphate, become part of DNA.

After much fiddling Romesberg’s group derived E. coli microbes that would take up X and Y when they were fed to the cells as part of their normal growth medium. The cells treat X and Y like the units they make themselves (A, C, G & T) and insert them in new DNA – so a stretch of genetic code may then read: A-C-G-T-X-T-A-C-Y-A-T-… And, once part of DNA, the novel units are passed on to the next generation.

Science fiction?
If this has you thinking creation and exploitation of entirely new life forms?!!’ you’re not alone. Seemingly Romesberg is frequently asked if he’s setting up Jurassic Park but, as he points out, the modified bugs he’s created survive only as long as they’re fed X and Y so if they ‘escape’ (being bugs this would probably be down the drain rather than over a fence), they die. Cunning eh?!!

Is this coming to a gene near you?
No. It is, however, clear that more synthetic bases will be made, expanding the power of the genetic code yet further. What isn’t yet known is what the cells will make of all this. In other words, the whole point of tinkering with DNA is to modify the code to make novel proteins. In the first instance the hope is that these might be useful in disease treatment. Rather longer-term is the notion that new organisms might emerge with specific functions – e.g., bugs that break down plastic waste materials.

At the moment all this is speculation. But what is now fact is amazing enough. After 4,000 million years since the first life-forms emerged, more than five billion different species have appeared (and mostly disappeared) on earth – all based on a genetic code of just four letters.

Now, in a small lab in southern California, Mother Nature has been given an upgrade. It’s going to be fascinating to see what she does with it!


Zhang, Y. et al. (2017). Proceedings of the National Academy of Sciences 114, 1317-1322.

Through the Smokescreen

For many years I was lucky enough to teach in a cancer biology course for third year natural science and medical students. Quite a few of those guys would already be eyeing up research careers and, within just a few months, some might be working on the very topics that came up in lectures. Nothing went down better, therefore, than talking about a nifty new method that had given easy-to-grasp results clearly of direct relevance to cancer.

Three cheers then for Mikhail Denissenko and friends who in 1996 published the first absolutely unequivocal evidence that a chemical in cigarette smoke could directly damage a bit of DNA that provides a major protection against cancer. The compound bound directly to several guanines in the DNA sequence that encodes P53 – the protein often called ‘the guardian of the genome’ – causing mutations. A pity poor old Fritz Lickint wasn’t around for a celebratory drink – it was he, back in the 1930s, that first spotted the link between smoking and lung cancer.

This was absolutely brilliant for showing how proteins switched on genes – and how that switch could be perturbed by mutations – because, just a couple of years earlier, Yunje Cho’s group at the Memorial Sloan-Kettering Cancer Center in New York had made crystals of P53 stuck to DNA and used X-rays to reveal the structure. This showed that six sites (amino acids) in the centre of the P53 protein poked like fingers into the groove of double-stranded DNA.

x-ray-picCentral core of P53 (grey ribbon) binding to the groove in double-stranded DNA (blue). The six amino acids (residues) most commonly mutated in p53 are shown in yellow (from Cho et al., 1994).

So that was how P53 ‘talked’ to DNA to control the expression of specific genes. What could be better then, in a talk on how DNA damage can lead to cancer, than the story of a specific chemical doing nasty things to a gene that encodes perhaps the most revered of anti-cancer proteins?

The only thing baffling the students must have been the tobacco companies insisting, as they continued to do for years, that smoking was good for you.

And twenty-something years on …?

Well, it’s taken a couple of revolutions (scientific, of course!) but in that time we’ve advanced to being able to sequence genomes at a fantastic speed for next to nothing in terms of cost. In that period too more and more data have accumulated showing the pervasive influence of the weed. In particular that not only does it cause cancer in tissues directly exposed to cigarette smoke (lung, oesophagus, larynx, mouth and throat) but it also promotes cancers in places that never see inhaled smoke: kidney, bladder, liver, pancreas, stomach, cervix, colon, rectum and white blood cells (acute myeloid leukemia). However, up until now we’ve had very little idea of what, if anything, these effects have in common in terms of molecular damage.

Applying the power of modern sequencing, Ludmil Alexandrov of the Los Alamos National Lab, along with the Wellcome Trust Sanger Institute’s Michael Stratton and their colleagues have pieced together whole-genome sequences and exome sequences (those are just the DNA that encode proteins – about 1% of the total) of over 5,000 tumours. These covered 17 smoking-associated forms of cancer and permitted comparison of tobacco smokers with never-smokers.

Let’s hear it for consistent science!

The most obvious question then is do the latest results confirm the efforts of Denissenko & Co., now some 20 years old? The latest work found that smoking could increase the mutation load in the form of multiple, distinct ‘mutational signatures’, each contributing to different extents in different cancers. And indeed in lung and larynx tumours they found the guanine-to-thymine base-pair change that Denissenko et al had observed as the result of a specific chemical attaching to DNA.

For lung cancer they concluded that, all told, about 150 mutations accumulate in a given lung cell as a result of smoking a pack of cigarettes a day for a year.

Turning to tissues that are not directly exposed to smoke, things are a bit less clear. In liver and kidney cancers smokers have a bigger load of mutations than non-smokers (as in the lung). However, and somewhat surprisingly, in other smoking-associated cancer types there were no clear differences. And even odder, there was no difference in the methylation of DNA between smokers and non-smokers – that’s the chemical tags that can be added to DNA to tune the process of transforming the genetic code into proteins. Which was strange because we know that such ‘epigenetic’ changes can occur in response to external factors, e.g., diet.

What’s going on?

Not clear beyond the clear fact that tissues directly exposed to smoke accumulate cancer-driving mutations – and the longer the exposure the bigger the burden. For tissues that don’t see smoke its effect must be indirect. A possible way for this to happen would be for smoke to cause mild inflammation that in turn causes chemical signals to be released into the circulation that in turn affect how efficiently cells repair damage to their DNA.


Sir Walt showing off on his return                         to England

Whose fault it is anyway?

So tobacco-promoted cancers still retain some of their molecular mystery as well as presenting an appalling and globally growing problem. These days a popular pastime is to find someone else to blame for anything and everything – and in the case of smoking we all know who the front-runner is. But although Sir Walter Raleigh brought tobacco to Europe (in 1578), it had clearly been in use by American natives long before he turned up and, going in the opposite direction (à la Marco Polo), the Chinese had been at it since at least the early 1500s. To its credit, China had an anti-smoking movement by 1639, during the Ming Dynasty. One of their Emperors decreed that tobacco addicts be executed and the Qing Emperor Kangxi went a step further by beheading anyone who even possessed tobacco.

And paying the price

And paying the price

If you’re thinking maybe we should get a touch more Draconian in our anti-smoking measures, it’s worth pointing out that the Chinese model hasn’t worked out too well so far. China’s currently heading for three million cancer deaths annually. About 400,000 of these are from lung cancer and the smoking trends mean this figure will be 700,000 annual deaths by 2020. The global cancer map is a great way to keep up with the stats of both lung cancer and the rest – though it’s not for those of a nervous disposition!


Denissenko, M.F. et al. ( (1996). Preferential Formation of Benzo[a]pyrene Adducts at Lung Cancer Mutational Hotspots in P53.Science 274, 430–432.

Cho, Y. et al. (1994). Crystal Structure of a p53 Tumor Suppressor-DNA Complex: Understanding Tumorigenic Mutations. Science, 265, 346-355.

Alexandrov, L.D. et al. (2016). Mutational signatures associated with tobacco smoking in human cancer. Science 354, 618-622.

Seeing a New World

May I wish readers a Happy New Year – and indeed extend my felicitations to non-readers with the hope that they too will become followers! What a good idea! Not least because I suspect many are viewing the new year with a mixture of anxiety and despair. But I can promise there’s nothing like the sanity of science to restore you after a few minutes contemplating how we’re doing on the economic and political fronts.

Your starter for 2017

By happy chance a few weeks ago I tried to explain how it’s now possible to ‘re-write the manual of life’ – that is, to engineer our DNA, to fix broken genes if you like. This means that, in theory, it’s possible to correct errors in our genetic code that cause genetic diseases. As there are over 6,000 of these and they include Down syndrome, cystic fibrosis and Alzheimer’s disease, there’s no need to say it’s important. There are several ways of going about this but the one I described is called CRISPR and it’s had a lot of media coverage.

Right on cue

Well done then Keiichiro Suzuki, Juan Carlos Belmonte and friends from the Salk Institute in California together with colleagues from other centres in Spain, Saudi Arabia and China for their December paper describing a new CRISPR twist. They used a rat model of retinitis pigmentosa, a genetic disease that is a major cause of inherited blindness, afflicting about one and a half million people worldwide (one in 4,000 in the UK).

The CRISPR-Cas9 system is great but it works best in dividing cells (e.g., in skin and gut that are renewing all the time) and it’s particularly useful for knocking out genes rather than inserting new DNA. The latest modification allows a new gene to be inserted into a specific site in the DNA of cells that are not dividing (e.g., those of the eye or brain).

The bits of CRISPR-Cas9, which insert DNA at very precise locations within the genome, are delivered to target cells as part of an inert virus. However, the package also includes DNA that encourages the cells to use a repair process that can be turned on even in non-dividing cells. So CRISPR-Cas9 cuts the cell’s DNA at an exact sequence and the cell then repairs the double-strand breaks (by a process called non-homologous end joining (NHEJ) that glues the broken ends directly together). Give the cell a new bit of DNA (e.g., your favorite gene) and that will get patched in – bear in mind that the cell doesn’t ‘know’ what it’s doing: it just tries to fix damaged DNA with whatever’s at hand.

And the target?

Retinitis pigmentosa occurs when a chunk of a gene called Mertk is lost. After quite a lot of experiments to show that their method worked, Suzuki, Belmonte & Co made a viral carrier that included a normal Mertk gene and injected it under the retina of rats with the disease. After about 5 weeks the rats were making Mertk RNA as a result of the gene being correctly ‘knocked-in’ to eye cells. The light-detecting region of the eye, greatly reduced by the disease, was significantly restored, with associated appearance of MERTK protein.

      Diseased    Normal     Treated                         Diseased         Normal         Treated


Left trio: Sections of the light-detecting layers of the eye in diseased (left), normal (centre) and diseased post-treatment rats (right). Right trio: corresponding fluorescence images showing MERTK expression (red: highlighted by white arrows); Cells labeled blue. (Suzuki et al. Nature 1–6 (2016) doi:10.1038/nature20565)

How did the rats see it?

Well, after treatment they were able to detect light and had significantly recovered their visual functions, albeit not to completely normal levels.

The usual caveats apply: the method isn’t hyper-efficient and a human treatment is still a long way off. Nevertheless, it’s a significant step.

The same group has also shown, using a way of re-programming the expression of just four genes, that it’s possible to arrest the signs of ageing. In other words, in mice this time, tinkering with these genes can increase lifespan – and yes, we have versions of these genes and in us they also control cell renewal.

So the New Year message is clear to see. If we can avoid turning the planet into a desert or blowing ourselves to smithereens the future is really rosy – and maybe even infinite!


Suzuki, K. et al. (2016). In vivo genome editing via CRISPR/Cas9 mediated homology-independent targeted integration. Nature 540, 144-149.

Ocampo, A. et al. (2016). In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming. Cell 167, 1719–1733.

Cockles and Mussels, Alive, Alive-O!

And so they are across the globe, not forgetting clams, a term that can cover all bivalve molluscs – a huge number of species (over 15,000), all having a two-part, hinged shell. The body inside doesn’t have a backbone, making it soft and edible on a scale of keeping-you-alive to orgasmic, depending on the consumer – oysters and scallops are part of the family.

Bivalves are particularly common on rocky and sandy coasts where they potter happily along, generally burrowing into sediment although some of them, scallops for instance, can swim. By and large their only problem is that humans like to eat them.

Clamming up

However, it gradually emerged in the 1970s that there was another cloud hovering over some of these gastronomic delights. Their commercial importance had drawn attention to the fact that soft-shell clams living along the east coast of North America, together with mussels on the west coast and cockles in Ireland, were dying in large numbers. The cause was an unusual type of cancer in which leukemia-like cells reproduce until they turn the blood milky and the animals die, in effect, from asphyxiation. In soft-shell clams, also known as sand gapers and steamers, the disease has spread over 1,500 km from Chesapeake Bay to Prince Edward Island.

A 2009 study had shown that as the disease progresses there is a rise in the number of blood cells that have abnormally high amounts of DNA (in clams typically four times the normal number of chromosomes – i.e. they’re tetraploid). In parallel with this change the cells make increasing amounts of an enzyme called reverse transcriptase (RT).

That was pretty surprising as RT does what its name suggests: reverses part of the central dogma of molecular biology (DNA makes RNA makes protein) by using RNA as a template to make DNA. RT is usually carried by viruses whose hereditary material is RNA (rather than DNA – so they’re called retroviruses). As part of their life cycle they turn their genomes into DNA that inserts into the host’s genome – which gets reproduced (as RNA) to make more viruses.

But how did RT get into clams? Enter Michael Metzger and Stephen Goff from Columbia University in New York, together with Carol Reinisch and James Sherry from Environment Canada, who began to unravel the mystery.

Jumping genes

Using high throughput sequencing they showed that clam genomes contain stretches of about 5,000 bases that came about when the RNA of a virus was copied into DNA by RT (reverse transcriptase) and then inserted into the host chromosome. Normal clams have from two to ten copies of this ‘repetitive element’ that Metzger & Co dubbed Steamer. That wasn’t too surprising as we have repetitive DNA too – it makes up about half the human genome. Many of these repeated sequences can move around within the genome – they’re often called ‘jumping genes’ – and it’s easy to see how this can happen when RT uses RNA to make DNA that can then pop into new sites in the genome. And you might guess that this process could damage the host DNA in ways that might lead to disease.

A long jump?

It turned out that the diseased clams had suffered massive amplification of Steamer to the extent that they carry 150 to 300 copies of the sequence. So that’s about 30 times as many Steamer DNAs being scattered across the clam genome – but how could that cause the same disease all the way from New York to Prince Edward Island? The answer came from peering into the DNA sequences of the tumour cells: they were virtually identical to each other – but they were different to those of their hosts! Meaning? The damage that led to leukemia, caused by shoe-horning 100s of extra copies of Steamer into clam genomes, only occurred once. And the staggering implication of that finding is that the cancer spread from a single ‘founder’ clam throughout these marine-dwelling molluscs. The resemblance to the way the cancer spreads in Tasmanian devils is striking.

Fishier and fishier

Fast forward to June 2016 and the latest contribution from the Metzger group reporting four more examples of transmissible cancer in bivalves – in mussels from British Columbia, in golden carpet shell clams from the Spanish coast and two forms in cockles.

Each appears to cause the same type of leukemia previously found in clams. The disease appears to be transmitted ‘horizontally’, i.e. by living cancer cells, descended from a single common ancestor, passing directly from one animal to another. Indeed, if you transplant blood cells from infected animals into normal clams they get leukemia.

 Species hopping

All that is quite amazing but the genetic analysis came up with an even more bizarre finding. In the golden carpet shell clams DNA from cancer cells showed no match with normal DNA from this species. It was clearly derived from a different species, which turned out to be the pullet shell clam – a species that, by and large doesn’t get cancer. So they have presumably 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!!clam-transfer-pic

Cancer cell transmission between different species of shellfish. Cancer cells can arise in one species (pullet shell clams) that do not themselves develop leukemia but are able to pass live cells to another species (golden carpet shell clams) that do get leukemia (Metzger et al. 2016).

We have no idea how the cancer cells survive transfer. It seems most likely that they are taken up through the siphons that molluscs use for feeding, respiration, etc. and then somehow get across the walls of the respiratory/digestive systems. In the first step they would have to survive exposure to sea water which contains a lot more salt than cells are happy in. The ‘isotonic’ saline used in drips to infuse patients contains 0.9% salt whereas seawater, with 3.5%, is ‘hypertonic’ – cells put in a hypertonic solution will shrink as water is drawn out of the cell into the surrounding solution. Presumably the cells shrivel up a bit but some at least take this in their stride and recover to reproduce in their new host. Equally obscure is how a species can protect itself from a cancer that it can pass to another species.

These amazing findings throw a different light on the care-free underwater life depicted in Disney’s The Little Mermaid, in which the popular song ‘Under the Sea’ fails to mention floating cancer.

Can this happen to us?!!

Well, not as far as we know. But the fact that the known number of cancers that can be passed from one animal to another has now risen to nine does make you wonder. However, there’s no evidence that it happens in humans in anything like the normal course of events. There are examples of person-to-person transfer, notably during organ transplantation, and there is one recent case of cancerous cells from a tapeworm colonising a human host. But these are very rare, the latter occurring in a patient with a severely weakened immune system, and there is no example of spread beyond two people.

Phew! What a relief! So now we can concentrate on following developments both in Tasmania and beneath the waves in the hope that, not only can we go on satisfying our lust for clam bakes and chowders, but that these incredible creatures will reveal secrets that will benefit mankind.


AboElkhair, M. et al. (2009). Reverse transcriptase activity associated with haemic neoplasia in the soft-shell clam Mya arenaria. Diseases of Aquatic Organisms 84, 57-63.

Arriagada, G. et al. (2014). Activation of transcription and retrotransposition of a novel retroelement, Steamer, in neoplastic hemocytes of the mollusk Mya arenaria. PNAS 2014 111 (39) 14175-14180; published ahead of print September 8, 2014, doi:10.1073/pnas.1409945111.

Metzger, M.J. et al. (2015). Horizontal Transmission of Clonal Cancer Cells Causes Leukemia in Soft-Shell Clams. Cell 161, 255–263.

Metzger, M.J. et al. (2016). Widespread transmission of independent cancer lineages within multiple bivalve species. Nature 534, 705–709.

Muehlenbachs, A. et al. (2015). Malignant Transformation of Hymenolepis nana in a Human Host. N Engl J Med 2015; 373:1845-1852.

Long-live the Revolutions!!

There’s a general view that most folk don’t know much about science and, because almost day by day, science plays a more prominent role in our lives, that’s considered to be a Bad Thing. Us scientists are therefore always being told to get off our backsides and spread the word – and I try to do my bit in Betrayed by Nature, in Secret of Life (a new book shortly to be published) and in these follow-up blogs.

We may be making some progress – and, I have to admit, television has probably done more than me – though I am available (t.v. & movie head honchos please note). As one piece of evidence you could cite the way ‘DNA’ has become part of the universal lexicon, albeit often nonsensically. As evidence I call Sony Corp. Chief Executive Kazuo Hirai, as reported in The Wall Street Journal: “I’ve said this from day one. Some things at Sony are literally written into our DNA …”

Well, of course, that’s gibberish Kazuo old bean – but we know what you mean. Or do we? Most probably couldn’t tell you what the acronym stands for – but that doesn’t matter if they can explain that it’s the stuff (a ‘molecule’ would be better still!) that carries the information of inheritance and, as such, is responsible for all life. Go to the top of the class those who add that the code is in the form of chemicals called bases and there are just four of them (A, C, G & T). Something that simple doesn’t seem enough for all life but the secret is lies in the vast lengths of DNA involved. The human genome, for example, is made up of three billion letters.

A little bit of what is now history …

In the mid-1980s a number of scientists from around the world began to talk about the possibility of working out the sequence of letters that make up human DNA and thus identifying and mapping all the genes encoded by the human genome. From this emerged The Human Genome Project, a massive international collaboration, conceived in 1984 and completed in 2003. I quite often refer to this achievement as the ‘Greatest Revolution’ – meaning the biggest technical advance in the history of biology.

As that fantastic enterprise steadily advanced to its triumphant conclusion, it was accompanied by a series of mini-revolutions in technology that sky-rocketed the speed of sequencing and slashed the cost – the combined effect being an increase the efficiency of the whole process of more than 100 million-fold.

Brings us to the present …

These quite astonishing developments have continued since 2003 such that by 2009 it was possible to sequence 12 individuals in one study. By August 2016 groups from all over the world, coming together under the banner of The Exome Aggregation Consortium (ExAC), have raised the stakes 5,000-fold by sequencing no fewer than 60,706 individuals.

The name of the outfit tells you that there’s what you might think of as a very small swizz here: they didn’t sequence all the DNA, just the regions that code for proteins (exomes) – only about 1% of the three billion letters. But what highlights the power of current methods is not only the huge number of individuals sequenced but the depth of coverage – that is, the number of times each base (letter) in each individual exome was sequenced. In effect, it’s doing the same experiment so many times that errors are eliminated. Thus even genetic variants in just one person can be picked out.


Sequence variants between individuals. For most proteins the stretches of genomic DNA that encode their sequence  are split into regions called exons. All the expressed genes in a genome make up the exomeBy repeated sequencing The Exome Aggregation Consortium have shown that genetic variants in even one person can be reliably identified. Variants from the normal sequence found in four people are shown in red, bold letters.

It turns out that there are about 7.5 million variants and they pop up remarkably often – at one in every eight sites (bases). About half only occur once (which illustrates why DNA fingerprinting, aka DNA profiling, is so sensitive). As Jay Shendure put it, this gives us a “glimpse of the bottom of the well of genetic variation in humans.”

One of the major results of this study is that, by filtering out common variants from those associated with specific diseases, it will help to pin down the causes of Mendelian diseases (i.e. genetic disorders caused by change or alteration in a single gene, e.g., cystic fibrosis, haemophilia, sickle-cell anaemia, phenylketonuria). It’s clear that, over the next ten years, tens of millions of human genomes will be sequenced which will reveal the underlying causes of the thousands of genetic disorders.

The prize … and the puzzle

The technology is breathtaking, the amount of information being accumulated beyond comprehension. Needless to say, private enterprise has leapt on the bandwagon and you can now get your genome sequenced by, for example, 23andMe who offer “a personalised DNA service providing information and tools for individuals to learn about and explore their DNA. Find out if you are at risk for passing on an inherited condition, who you’re related to etc.” All for a mere $199!!

But you could say that the endpoint – the reason for grappling with DNA in the first place – is easy to see: eventually we will be able to define the molecular drivers of all genetic diseases and from that will follow ever improving methods of treatment and prevention.

Nevertheless, in that wonderful world I suspect we will still find ourselves brought up short by the underlying question: how one earth does DNA manage to carry the information necessary for all life?

For those who like to ponder such things, in the next piece we’ll try to help by looking at DNA from a different angle.


Ng, SB. et al. (2009). Nature 461, 272-276.

Lek, M. et al. (2016). Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291.

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.



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:

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.

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.

Dennis’s Pet Menace

As it happened, I’d already agreed to appear on Jeremy Sallis’ Lunchtime Live Show on BBC Radio Cambridgeshire – the plan being just to chat about cancery topics that might be of interest to listeners. Which would have been fine – if only The World Health Organization had left us in peace. But of course they chose last Tuesday to publish their lengthy cogitations on the subject of whether meat is bad for us – i.e. causes cancer.

Cue Press extremism: prime example The Times, quite predictably – they really aren’t great on biomedical science – who chucked kerosene on the barbie with the headline ‘Processed meats blamed for thousands of cancer deaths a year’.

But – to precise facts – and strictly it’s The International Agency for Research on Cancer, the cancer agency of the World Health Organization (WHO), that has ‘evaluated the carcinogenicity of the consumption of red meat and processed meat.’

But hang on … haven’t we been here before?

Indeed we have. As long ago as January 2012 in these pages we commented on the evidence that processed meat can cause pancreatic cancer and in May of the same year we reviewed the cogitations of the Harvard School of Public Health’s 28 year study of 120,000 people that concluded eating red meat contributes to cardiovascular disease, cancer and diabetes. To be fair, that history partially reflects why the WHO Working Group of 22 experts from 10 countries have taken so long to go public: they reviewed no fewer than 800 epidemiological studies! However, as the most frequent target for study was colorectal (bowel) cancer, that was the focus of their report released on 26th October 2015.

So what are we talking about?

Red meat, which means any unprocessed mammalian muscle meat, e.g., beef, veal, pork, lamb, mutton, horse or goat meat, that we usually cook before eating.

Processed meat: any meat not eaten fresh that has been salted, cured, smoked or whatever and commonly treated with chemicals to enhance flavour and colour and to prevent the growth of bacteria.

What did they say?

Processed meat is now classified as carcinogenic to humans – that is it goes into the top group (Group 1) of agents that cause cancer.

Red meat is probably carcinogenic to humans (Group 2A). Group 2B is for things that are possibly carcinogenic to humans.


Because 12 of the 18 studies they reviewed showed a link between consumption of processed meat and bowel cancer and because it’s known that agents commonly added to processed meat (nitrates and nitrites) can, when we eat them, turn into chemicals that can directly damage DNA, i.e. cause mutations and hence promote cancers.

For red meat 7 out of 15 studies showed positive associations of high versus low consumption with bowel cancer and there is strong mechanistic evidence for a carcinogenic effect i.e. when meat is cooked genotoxic (i.e. DNA-damaging) chemicals can be generated. They put red meat in the probably group because several of the studies that the Working Group couldn’t fault – and therefore couldn’t leave out – showed no association.

Stop woffling

My laptop likes to turn ‘woffling’ into ‘wolfing’. Maybe it’s trying to tell me something.

But is The WHO trying to tell us something specific about wolfing? To be fair, they have a go by estimating that every 50 gram portion of processed meat (say a couple of slices of bacon) eaten daily increases the risk of bowel cancer by about 18%. For red meat the data ‘suggest’ that the risk of bowel cancer could increase by 17% for every 100 gram portion eaten daily.

And what might that mean?

In the UK about 6 people in 100 get bowel cancer: if you take The WHO maximum estimate and have everyone eat 50 grams of processed meat every day of their lives such that 18% more of them would get bowel cancer, the upshot would be 7 people in 100 rather than 6. So it’s a small rise in a relatively small risk.

As the report points out, the Global Burden of Disease Project reckons diets high in processed meat cause about 34,000 cancer deaths per year worldwide and, if the reported associations hold up, the figure for red meat would be 50,000. Compare those figures with smoking that increases the risk of lung cancer by 20-fold and The WHO’s estimate of up to 6 million cancer deaths per year globally caused by tobacco use and 600,000 per year by alcohol consumption.

All of which suggests that it isn’t very helpful to lump meat eating, tobacco and asbestos in the same cancer-causing category and that The WHO could do worse than come up with a new classification system.

And the message?

Unchanged. Remember mankind evolved into the most successful species on the planet as a meat eater. As the advert used to say: It looks good, it tastes good and by golly it does you good – not least as a source of protein, vitamins and other nutrients. Do some exercise and eat a balanced diet – just in case you’ve forgotten, that means limit the amount of red meat (The WHO suggests no more than 30 grams a day for men, 25 g for women) so try fish, poultry, etc. Stick with the ‘good carbs’ (vegetables, fruits, whole grains, etc.), cut out the ‘bad’ (sugar – see Biting the Bitter Bullet), eat fishy fats not saturated fats and, to end on a technical note, don’t pig out.


‘The Divine Swine’ Castelnuovo Rangone, Italy

Meanwhile back on the Beeb

When the meat story broke I was a bit concerned that we might end up spending the whole of Lunchtime Live on how many bangers are lethal – especially as we were taking calls from listeners. Just in case things became a bit myopic I had Rasher up my sleeve. Rasher, you may recall, was Dennis the Menace‘s pet pig (in the The Beano‘s comic strip) who had a brother (Hamlet), a sister (Virginia Ham) and various other porky rellos. To bring it up to date we’d have introduced Sam Salami and Frank Furter and, of course, Rasher’s grandfather who was the model for the bronze statue named ‘The Divine Swine’ to be found in the little town of Castelnuovo Rangone in Pig Valley, Italy, the home of Parma ham.

But I shouldn’t have worried. All was well in the hands of Jeremy Sallis who, being a brilliant host, ensured that we mainly chatted about meatier matters than what to have for breakfast.


Press release: IARC Monographs evaluate consumption of red meat and processed meat.

Q&A on the carcinogenicity of the consumption of red meat and processed meat.

Carcinogenicity of consumption of red and processed meat. Published online October 26, 2015