Food Fix For Pharma Failure

 

If you held a global quiz, Question: “Which biological molecules can you name?” I guess, setting aside ‘DNA‘, the top two would be insulin and glucose. Why might that be? Well, the World Health Organization reckons diabetes is the seventh leading cause of death in the world. The number of people with diabetes has quadrupled in the last 30 years to over 420 million and, together with high levels of blood glucose (sugar), it kills nearly four million a year.

There are two forms of diabetes: in both the level of glucose in the blood is too high. That’s normally regulated by the hormone insulin, made in the pancreas. In Type 1 diabetes insulin isn’t made at all. In Type 2 insulin is made but doesn’t work properly.

When insulin is released into the bloodstream it can ‘talk’ to cells by binding to protein receptors that span cell membranes. Insulin sticks to the outside, the receptor changes shape and that switches on signalling pathways inside the cell. One of these causes transporter molecules to move into the cell membrane so that they can carry glucose from the blood into the cell. When insulin doesn’t work it is this circuit that’s disrupted.

Insulin signalling. Insulin binds to its receptor which transmits a signal across the cell membrane, leading to the activation of the enzyme PIK3. This leads indirectly to the movement of glucose transporter proteins to the cell membrane and influx of glucose.

So the key thing is that, under normal conditions, when the level of blood glucose rises (after eating) insulin is released from the pancreas. Its action (via insulin receptors on target tissues e.g., liver, muscle and fat) promotes glucose uptake and restores normal blood glucose levels. In diabetes, one way or another, this control is compromised.

Global expansion

Across most of the world the incidence of diabetes, obesity and cancer are rising in parallel. In the developed world most people are aware of the link between diabetes and weight: about 90% of adults with diabetes are overweight or obese. Over 2 billion adults (about one third of the world population) are overweight and nearly one third of these (31%) are obese — more than the number who are underweight. The cause and effect here is that obesity promotes long-term inflammation and insulin resistance — leading to Type 2 diabetes.

Including cancer

The first person who seems to have spotted a possible connection between diabetes and cancer was the 19th-century French surgeon Theodore Tuffier. He was a pioneer of lung and heart surgery and of spinal anaesthesia and he’s also a footnote in the history of art by virtue of having once owned A Young Girl Reading, one of the more famous oil paintings produced by the prolific 18th-century artist Jean-Honoré Fragonard (if you want to see it head for the National Gallery of Art in Washington DC). Tuffier noticed that having type 2 diabetes increased the chances of patients getting some forms of cancer and pondered whether there was a relationship between diabetes and cancer.

It was a good question then but it’s an even better one now when this duo have become dominant causes of morbidity and mortality worldwide.

We now know that being overweight increases the risk of a wide range of cancers including two of the most common types — breast and bowel cancers. Unsurprisingly, the evidence is also clear that diabetes (primarily type 2) is associated with increased risk for some cancers (liver, pancreas, endometrium, colon and rectum, breast, bladder).

With all this inter-connecting it’s perhaps not surprising that the pathway by which insulin regulates glucose also talks to signalling cascades involved in cell survival, growth and proliferation — in other words, potential cancer initiators. The central player in all this is a protein called PIK3 (it’s an enzyme that adds phosphate groups (so it’s a ‘kinase’) to a lipid called phosphatidylinositol bisphosphate, an oily, water-soluble component of the plasma membrane). It’s turned out that PIK3 is one of the most commonly mutated genes in human cancers — e.g., PIK3 mutations occur in 25–40% of all human breast cancers.

Signalling pathways switched on by mutant PIK3. A critical upshot is the activation of cell survival and growth that leads to cancer.

Accordingly, much effort has gone into producing drugs to block the action of PIK3 (or other steps in this signal pathway). The problem is that these have worked as cancer treatments either very variably or not at all.

The difficulty arises from the inter-connectivity of signalling that we’ve just described: a drug blocking insulin signalling causes the liver to release glucose and prevents muscle and fats cells from taking up glucose. Result: blood sugar levels rise (hyperglycaemia). This effect is usually transient as the pancreas makes more insulin that restores normal glucose levels.

Blockade of mutant PIK3 by an inhibitor. This blocks the route to cancer but glucose levels rise in the circulation (hyperglycaemia) promoting the release of insulin (top). Insulin can now signal through the normal pathway (bottom), overcoming the effect of the anti-cancer drug. Note that the cell has two copies of the PIK3 gene/protein, one of which is mutated, the other remaining normal.

Is our journey really necessary?

By now you might be wondering whether there is anything that makes grappling with insulin signaling worth the bother. Well, there is — and here it is. It’s a recent piece of work by Benjamin Hopkins, Lewis Cantley and colleagues at Weill Cornell Medicine, New York who looked at ways of getting round the insulin feedback response so that the effect of PIK3 inhibitors could be boosted.

Sketch showing the effect of diet on the potency of an anti-cancer drug in mice. The red line represents normal tumour growth. The black line shows the effect of PIK3 blockade when the mice are on a ketogenic diet: tumour growth is suppressed. On a normal diet the drug alone has only a slight effect on tumour growth. Similar results were obtained in a variety of model tumours (Hopkins et al., 2018).

They first showed that, in a range of model tumours in mice, insulin feedback caused by blockade of PIK3 was sufficient to switch on signalling even in the continued presence of anti-PIK3 drugs. The really brilliant result was that changing the diet of the mice could offset this effect. Switching the mice to a high-fat, adequate-protein, low-carbohydrate (sugar) diet essentially stopped the growth of tumours driven by mutant PIK3 treated with PIK3 blockers. This is a ketogenic (or keto) diet, the idea being to deplete the store of glucose in the liver and hence limit the rise in blood glucose following PIK3 blockade.

Giving the mice insulin after the drug drastically reduces the effect of the PIK3 inhibitor, supporting the idea that that a keto diet improves responses to PIK3 inhibitors by reducing blood insulin and hence its capacity to switch on signalling in tumour cells.

A few weeks prior to the publication of the PIK3 results another piece of work showed that adding the amino acid histidine to the diet of mice can increase the effectiveness of the drug methotrexate against leukemia. Methotrexate was one of the first anti-cancer agents to be made and has been in use for 70 years.

These are really remarkable results — as far as I know the first time diet has been shown to influence the efficacy of anti-cancer drugs. It doesn’t mean that all tumours with mutations in PIK3 have suddenly become curable or that the long-serving methotrexate is going to turn out to be a panacea after all — but it does suggest a way of improving the treatment of many types of tumour.

References

Hopkins, B.D. et al. (2018). Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature 560, 499-503.

Kanarek, N. et al. (2018). Histidine catabolism is a major determinant of methotrexate sensitivity. Nature 559, 632–636.

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Now You See It

 

In the pages of this blog we’ve often highlighted the power of fluorescent tags to track molecules and see what they’re up to. It’s a method largely pioneered by the late Roger Tsien and it has revolutionized cell biology over the last 20 years.

In parallel with molecular tagging has come genetic engineering that permits novel genes, usually carried by viruses, to be introduced to cells and animals. As we saw in Gosh! Wonderful GOSH and Blowing Up Cancer, various ‘virotherapy’ approaches have been used with some success to treat leukemias and skin cancers and a trial is underway in China treating metastatic non-small cell lung cancer.

A major aim of genetic engineering is to be able to control the expression of novel genes (i.e. protein production from the encoding DNA sequence) that have been introduced into an animal — in the jargon, to ‘switch’ on or off at will. That can be done but only by administering a drug or some other regulator, either in drinking water, by injection or squirting directly into the lungs. An ideal would be something that’s more controlled and less invasive. How about shining a light on the relevant spot?!

Wacky or what?

That may sound as though we’re veering towards science fiction but reflect for a moment that every animal with vision, however rudimentary, sees by transforming light entering the eyes into electrical signals that the brain turns into a picture of the world around them. This relies on photoreceptor proteins that span the membranes of retinal cells.

How vision works. Light passes through the lens and falls on the retina at the back of the eye. The photoreceptor cells it activates are rod cells (that respond to low light levels — there’s about 100 million of them) and cone cells (stimulated by bright light). Sitting across the membranes of these cells are photoreceptor proteins — rhodopsin in rods and photopsin in cones. Photoreceptor proteins change shape when light falls on them — the driver for this being a small chemical attached to the proteins called retinal, one of the many forms of vitamin A. This shape change allows the proteins to ‘talk’ to the inside of the cell, i.e. to interact with other proteins to switch on enzymes and change the level of ions (sodium and calcium). The upshot is that the signal is passed through neural cells in the optic nerve to the brain where the incoming light signals are processed into the images that we perceive. © Arizona Board of Regents / ASU Ask A Biologist.

The seemingly far-fetched notion of controlling genes by light was floated by Francis Crick in 1999. The field was launched in 2002 by Boris Zemelman and Gero Miesenböck who engineered neurons to express one form of rhodopsin. This gave birth to the subject of optogenetics — using light to control cells in living tissues that have been genetically modified to express light-sensitive ion channels such as rhodopsin. By 2010 optogenetics had advanced to being the ‘Method of the Year’ according to the research journal Nature Methods.

Dropping like flies

One of the most dramatic demonstrations of the power of optogenetics has come from Robert Kittel and colleagues in Würzburg and Göttingen who made a mutant form of a protein called channelrhodopsin-1 (found in green algae) and expressed it in fruit flies (Drosophila melanogaster). The mutant protein (ChR2-XXL) carries very large photocurrents of ions (critically sodium and calcium) with the result that photostimulation can drastically change the behaviour of freely moving flies.

Light-induced stimulation of motor neurons in adult flies expressing a mutant form of rhodopsin ChR2-XXL. Click to run movie.

Left hand tube: Activation of ChR2-XXL in motor neurons with white light LEDs caused reversible immobilization of adult flies. In contrast (right hand tube) flies expressing normal (wild-type) channelrhodopsin-2 showed no response. From Dawydow et al., 2014.

Other optogenetic experiments on flies can be viewed on You Tube, e.g., the TED talk of Gero Miesenböck and the Manchester Fly Facility video of fly maggots, engineered to have a channel protein (channelrhodopsin) in their neurons, responding to blue light.

Of flies … and mice … and men

This is stunning science and it’s opened a new vista in neurobiology. But what about the things we’re concerned with in these pages — treating diseases like diabetes and cancer?

Scheme showing how genetic engineering can make the release of insulin from cells controllable by light. Normally cells of the pancreas (beta cells) take up glucose when its level in the circulation rises (via a glucose transporter protein). The rise in glucose triggers ATP production in the cell. This in turn causes potassium channels in the membrane to close (called depolarization) and this opens calcium channels. The increase in calcium in the cell drives insulin secretion. From Kushibiki et al., 2015.

The left-hand scheme above shows how glucose triggers the pancreas to produce the hormone insulin. Diabetes occurs when either the pancreas doesn’t make enough insulin or when cells of the body don’t respond properly to insulin by taking up glucose.

As a first step to see whether optogenetic regulation of calcium levels in pancreatic cells could trigger insulin release, Toshihiro Kushibiki and colleagues at the National Defense Medical College in Saitama, Japan engineered the channelrhodopsin-1 protein into mouse cells and hit them with laser light of the appropriate frequency. An hour after a short burst of light (a few seconds) the insulin levels had doubled.

The photo below shows a clump of these cells: the nuclei are blue and the channel protein (yellow) can be seen sitting across the cell membranes.

 

Cells expressing a fluorescently tagged channelrhodopsin protein (yellow). Nuclei are blue. From Kushibiki et al., 2015.

 

 

To show that this could work in animals they suspended the engineered cells in a gel and inoculated blobs of the goo under the skin of diabetic mice. Laser burst again: blood glucose levels fell and they showed this was due to the irradiated, implanted cells producing insulin.

Fast forward three years

Those brilliant results highlighted the potential of optogenetic technology as a completely novel approach to a disease that afflicts over 300 million people worldwide.

Scheme showing a Smartphone can be used to regulate the release of insulin from engineered cells implanted in a mouse with diabetes. The key events in the cell are that the light-activated receptor turns on an enzyme (BphS) that in turn controls a transcription regulator (FRTA) that binds to a DNA construct to switch on the Gene Of Interest (GOI) — in this case encoding insulin. (shGLP1, short human glucagon-like peptide 1, is a hormone that has the opposite effect to insulin). From Shao et al., 2017.

In a remarkable confluence of technologies Jiawei Shao and colleagues from a number of institutes in Shanghai, including the Shanghai Academy of Spaceflight Technology, and from ETH Zürich have recently published work that takes the application of optogenetics well and truly into the twenty-first century.

They figured that, as these days nearly everyone lives with their smartphone, the world could use a diabetes app. Essentially they designed a home server SmartController to process wireless signals so that a smartphone could control insulin production by cells in gel capsules implanted in mice. There are differences in the genetic engineering of these cells from those used by Kushibiki’s group but the critical point is unchanged: laser light stimulates insulin release. The capsules carry wirelessly powered LEDs.

The only other thing needed is to know glucose levels. Because mice are only little and they’ve already got their gel capsule, rather than implanting a monitor they took a drop of blood from the tail and used a glucometer. However, looking ahead to human applications, continuous glucose monitors are now available that, placed under the skin, can transmit a radio signal to the controller and, ultimately, it will be possible for the gel capsules to have a built-in battery plus glucose sensor and the whole thing could work automatically.

Any chance of illuminating cancer?

This science is so breathtaking it seems cheeky to ask but, well, I’d say ‘yes but not just yet.’ So long as the ‘drug’ you wish to use can be made biologically (i.e. from DNA by the machinery of the cell), rather than by chemical synthesis, Shao’s Smartphone set-up can readily be adapted to deliver anti-cancer drugs. This might be hugely preferable to the procedures currently in use and would offer an additional advantage by administering drugs in short bursts of lower concentration — a regimen that in some mouse cancer models at least is more effective.

References

Dawydow, A., Kittel, R.J. et al., 2014. Channelrhodopsin-2–XXL, a powerful optogenetic tool for low-light applications. PNAS 111, 13972-13977.

Kushibiki et al., (2015). Optogenetic control of insulin secretion by pancreatic beta-cells in vitro and in vivo. Gene Therapy 22, 553-559.

Shao, J. et al., 2017. Smartphone-controlled optogenetically engineered cells enable semiautomatic glucose homeostasis in diabetic mice. Science Translational Medicine 9, Issue 387, eaal2298.

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.

Why?

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.

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‘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.

References

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. www.thelancet.com/oncology Published online October 26, 2015

Scandinavian Somersaults … or As You Were?

Talking about diets in the last post may have brought to mind the publicity about weight-reducing diets created by a recent Swedish study Dietary Treatment for Obesity.”

This report, incorrectly described by some of the press as providing national guidelines, has been interpreted as earth-shaking in turning conventional wisdom on its head by advocating a switch from low-fat to high-fat/low-carb nutrition.

lg-raspberry_chipotle_meatballsHelp yourself: Swedish meat balls:

pork and beef with lots of cream

But did it really say anything remotely revolutionary? Well, no. First, it was concerned only with diets aimed at reducing weight for obese people – and the central point was that a low-carbohydrate, high-fat diet, was the most effective in the short-term – over about 6 months – after which there’s not much difference compared with other dietary regimens.

So to summarise: eating lots of sugar and starch is bad for you – as anyone with much of a clue about metabolism knew anyway (see Biting the Bitter Bullet & A Small Helping For Australia) – and substituting artificial sweeteners won’t help either (The Best Laid Plans in Mice and Men..).

ShowImageVB.aspxA reminder from The Food Standards Agency

 References

SBU. Food in obesity. A systematic literature review. Stockholm: Swedish Council on Technology Assessment in Health Care (SBU); 2013. SBU Report No. 218. ISBN 978-91-85413-59-1.

http://healthimpactnews.com/2013/sweden-becomes-first-western-nation-to-reject-low-fat-diet-dogma-in-favor-of-low-carb-high-fat-nutrition/

Our Inner Self

Richard Gettner is the anti-hero of Christopher Fry’s wonderful play The Dark is Light Enough, set in the Austro-Hungarian war of 1848. Viewing himself as a failed author, failed husband and all-round disaster, he’s just absented himself from the Austrian Army on the basis of not being too nifty at soldiering either. Their minions are hot on his heels, intent on meting out the retribution that the military traditionally reserve for deserters, and he’s taken refuge in the family home of his former wife. In a tête á tête with her she rebukes him for his knack of self-destruction and points out that his book was actually quite well received and wasn’t really a failure. All Gettner’s frustration then bursts forth in a tirade of brutal philosphising:

‘Is there another

Word in the language so unnecessary

As ‘fail’ or ‘failure’?

No one has ever failed to fail in the end;

And for the very evident reason

That we’re made in no fit proportion

To the universal occasion; which, as all

Children, poets and myth-makers know,

Was made to be inhabited

By giants, fiends, and angels of such size

The whole volume of human generations

Could be cupped in their hands;

And very ludicrous it is to see us,

With no more than enough spirit to pray with,

If as much, swarming under gigantic

Stars and spaces.’

Fry deserves to be remembered as one of the great poetic wordsmiths of the English language, if only for The Dark is Light Enough but, had he known that nine out of ten cells in our bodies are bugs, he might have added a final blast to his demolition of the human condition:

Our failings should not surprise as we are but a sinister symbiosis,

More bacterial than human,

Helpfully poised such that when our hour is done

The microbial hordes surge forth to reduce us to our component parts.

bacteria and virus cartoon

The range of the hordes

Our rising preoccupation with the bug army (see it’s a small world & The Best Laid Plans In Mice and Men …) has been promoted by several recent studies that have propelled our ‘inner organism’ from the bowels of biology into the limelight. The story is somewhat fragmented but it’s a good time to see if we can make sense of the current threads.

We’ve known for many years that a motley collection of microorganisms are happy residents in most of our nooks and crannies, ranging from tummy buttons and through the skin, to saliva and our guts. They include bacteria and fungi, they’ve become known as the human microbiome (or microbiota), are said to outnumber human cells 10 to 1 and, all-told, can be viewed as a co-evolved ‘super-organism’ that has many benefits, including making our metabolism more efficient and hence improving nutrition. However, as with everything else in biology, this close relationship is a balancing act, the disturbance of which carries risks for disease development.

It’s critical to note that this vast microbial army, toiling away on our behalf in the dungeon of our innards, mostly dwelling in our gut, is a really mixed lot. It’s estimated to include about 700 different species of bacteria, of which perhaps thirty or forty species make up the bulk. It’s a bit like a mini Great Barrier Reef, well known as the world’s largest coral reef system and extraordinary in that, although it’s made up of billions of tiny organisms, the thing can behave in an integrated way, most dramatically illustrated by mass spawning.

Within the gut there are two major sub-families of microorganisms (Bacteroidetes (Bs) and Firmicutes (Fs)). Although more close-knit genetically speaking, each of these still includes many different classes of microbe. So, they’re a bit of a rabble but, by and large, not only are they harmless, they actually play a vital part in keeping us healthy.

Bacterial army manoeuvres

The power of DNA sequencing means that we can now interrogate our inner armies as to their make up under different conditions, because each type of microbe has a distinctive genome. The first thing to emerge is a dramatic shift in the balance between the major sub-families in obese individuals, be they mice or humans. That is, obese animals have about half the number of Bs and double that of Fs, compared to normal. And the link here is that the bug switch alters the pool of genes available, the upshot being increased energy harvest from nutrients consumed. In other words the switch helps animals get fatter.

It’s possible to breed mice that do not have any gut bugs and ask what happens when you transfer a colony from another animal. Bacteria-free mice on receipt of a normal gut army promptly double body fat: microbiota transferred from obese mice makes ’em twice as fat and, remarkably, human gut microbes from someone who’s obese also makes mice obese, if fed a high-fat rather than a normal diet.

Chemical warfare

Because we use antibiotics on a massive scale to control infections, we might ask whether they cause the good guys to suffer what the military call collateral damage – the point being that antibiotics don’t target bacteria on the basis of whether they’re good for us or potentially fatal. Inevitably, it turns out that ‘good guys’ do get hit by some antibiotics, and when this happens mice gain weight and build up fat. Unsurprisingly, a high-fat diet makes things worse. The sequence is that the drug changes the balance in microbiota before mice become obese and – a real shock – one course of antibiotic treatment imprints these effects on the animal permanently: it acts for life.

To clever for our own good

In our panic to avoid obesity and still pander to our sweet tooth, mankind has taken to using artificial sweeteners on a massive scale in the mistaken belief that these low-calorie agents do no harm. Only recently has this come to light as yet another example of the old adage about there being no such thing as a free lunch. It’s remarkable: saccharin, the most commonly used artificial sweetener, causes big shifts in the proportions of different types of gut bacteria – some increasing whilst others go down – the overall effect again being much more efficient energy harvesting from food. This is a direct effect of saccharin on the bugs, blocked by commonly used antibiotics.

The story so far

The regiments from which our foot soldiers are drawn (i.e. the species that form the microbiota) affect our metabolism and in particular can influence obesity – and that’s inextricably linked with type 2 diabetes and heart disease. With that in mind, it seems obvious that upsetting them with drugs is a risky business. What’s more, seemingly harmless food supplements can also be fraught with danger.

Marching to a beat

Yet another amazing feature of our inner army is that it keeps time. That is, the abundance of different sub-types fluctuates in synchrony with the day/night cycle. Put another way, it marches to a circadian rhythm along with many other physical, mental and behavioral changes that respond mainly to light – and hence roughly follow a 24-hour cycle. These can be big changes in composition: a particular type of bug can double in amount in 6 hours and return to its initial level by 6 hours later. One of the most familiar examples of the importance of biological rhythms comes from upsetting them by flying long distances on an east–west axis. Sure enough, mice have the same problem and, just like us, their clock is disturbed by jet lag (rather than shuttling them business class across the Atlantic you can simulate the effect simply by shifting the light-dark cycle under which they live forwards or backwards by 8 hours every three days). This largely blocks microbiota rhythmicity, the overall effect being to reduce the total number of bacteria. This in turn raises blood sugar level and the mice become obese. These events are absolutely dependent on what has happened to the microbiota because they are replicated in germ-free mice after transfer of jet-lagged faeces.

That’s more astonishing than might appear at first glance because it places the daily variation in gut bug populations alongside the basic circadian rhythms of the sleep-wake cycle, body temperature and other important functions. Circadian rhythms are driven by a ‘master clock’ in the brain that coordinates all the body clocks so that they are in synch. Four proteins are at the heart of the clock (CLOCK and BMAL1, highly expressed during the light phase, and cryptochromes (CRYs) and period proteins (PERs) expressed in the dark phase). These regulate the expression of many genes, thereby controlling the overall response (see Twenty More Winks). The implication is, therefore, that far from being a kind of add-on that occasionally gets upset, our microbiota play central role in a healthy body.

A recent example of it doing just that comes from another mouse model showing our ‘inner organism’ acting to protect against bacteria from the outside world. In response to infection, cells that line the small intestine switch on the production of a particular sugar (fucose): that is then released from the cells and consumed by members of the microbiota – this novel energy source seemingly helping the host to survive the onslaught of infectious microorganisms.

And finally …

All this stuff about germs being our best friends is riveting but what about the important question? Well, there appears to be a complex interaction between diet, microbial metabolism and colorectal cancer, with bacteria able to make some agents that protect against cancer and some others that drive carcinogenesis. There’s evidence that a wide range of tumours can be promoted by transferring microbiota to germ-free mice and, on the other hand, that depleting intestinal bacteria reduces the development of liver and colon cancers.

Space invaders

Personal space is, apparently, a big thing for many of us these days. So big that ‘scientists’ have had a go at measuring it – they never miss an opportunity do they? Actually, boffins being boffins, they measured something called the defensive peripersonal space (DPPS) – a ‘vital safety margin surrounding the body’ – by sticking a pair of electrodes to the wrists of volunteers who held their hands different distances from their faces whilst receiving bursts of current through the electrodes. That made them blink (!) and the nearer the hand to the face the more they blinked, as the shock was perceived to be a greater threat to their face. There is, seemingly, a sharp boundary: up to somewhere between 20 cm and 40 cm is a high-risk area where we get very aerated: beyond that we don’t much care – with large personal variations depending on how twitchy you are. Debrett’s, which styles itself as the arbiter of society etiquette, has a simpler test, its distilled wisdom revealing that if you can feel the warmth of someone’s anxious breath upon your face, then you’re standing too close.

With all this neurosis it’s probably a good job no one mentioned our inner army: a ten-to-one cellular takeover (albeit that bugs are much smaller) is not so much a bit of heavy breathing as a blitzkrieg. Even so, it’s a delicately poised occupation upon which we depend for survival – and it’s one that we disturb at our peril.

References

Sambo, C.F. and Iannetti, G.D. (2013). Better Safe Than Sorry? The Safety Margin Surrounding the Body Is Increased by Anxiety. The Journal of Neuroscience 33, 14225-14230; doi: 10.1523/JNEUROSCI.0706-13.2013.

The Best Laid Plans In Mice and Men …

I never thought I’d find myself indebted to one R. Burns, said to be Scotland’s national poet, but as a title for today’s piece it’s hard to avoid a mild bit of adaptive plagiarism. And after all, if John Steinbeck could do it …

Artificial sweeteners are wonderful things …

The next thing to do is to pass up all pretence at suspense and give the upshot of a remarkable new bit of work first. The story is of artificial sweeteners (non-caloric artificial sweeteners: NAS for short – most commonly saccharin) – among the most widely used food additives worldwide. Introduced over a century ago, they’ve long been considered great as they pander to our sweet teeth yet are low on calories – what can possibly go wrong?

Saccharin  StructureSweet'N Low

Well, according to Jotham Suez and his pals in The Weizmann Institute, Israel, quite a lot, once you get round to looking in the right places. They found that artificial sweeteners, particularly saccharin, make normal folk glucose intolerant (i.e. cause metabolic conditions – including diabetes – in which blood glucose levels are raised, aka hyperglycemia). Moreover, they do so by changing the make up of the bacteria in our gut (our intestinal microbiota – we’ve already met these guys in it’s a small world). The effects of NAS are reversed by antibiotics which, as we described in it’s a small world, can have drastic, permanent effects on our insides.

It’s a real shocker because, put another way, it shows NAS can dirDiet Coke etcectly drive the very outcomes we’re trying to avoid – diabetes and obesity.

How do they do it?

Suez & Co first showed that saccharin increases blood glucose in mice (glucose intolerance). Treatment with commonly used antibiotics (e.g., ciprofloxacin) blocks this effect. Sequencing DNA extracted from faeces revealed big shifts in the proportions of different types bacteria (taxa) – with some increasing whilst others went down. The overall effect is that the intestinal bugs (microbiota) as a whole became much more efficient at energy harvesting from food (e.g., producing more short-chain fatty acids) – an effect known to be associated with obesity in both mice and humans.

Obese miceDirect or indirect?

To show whether saccharin does this by directly acting on gut bugs they grew samples of faeces in the lab with and without added saccharin and – you’ve guessed it – the bug balance changed: Firmicutes down, Bacteroidetes up (from 89 to 79% and 6 to 22%, respectively). Transferring the saccharin-treated microbiota to germ-free (normal) mice made them glucose intolerant.

Lolli the Saccharin by Trinity FateRe-think required

The upshot of all this is that NAS may be doing the very thing we’re trying to avoid. Suez et al. note that the cult of NAS use has coincided with the epidemics of diabetes and obesity – but their results suggest very strongly that, far from being coincidence, it is yet another example of optimism and our hunger for easy solutions diverting our attention from our ignorance of the underlying science.

Grim reaperSo the message is there isn’t a short-cut to dealing with our sugar craving – if we aren’t to go on making ourselves very ill on a big scale we just have to show more self-discipline.

Reference

Suez , J. et al. (2014). Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature 514, 181-186.

A Small Helping For Australia

There’s an awful lot of very good things in Australia. Australians for a start. They’re just so kind, open, welcoming and accommodating it makes touring round this vast land a joy. Not merely do they cheerfully find a way to fix anything you want but they’re so polite that no one’s drawn attention to my resemblance to a scientific version of those reconstructed geriatric pop groups (viz the Rolling Stones or whatever) staggering round the place on their Zimmer frames. And they say wonderful things about my talks – that’s how charming they are!!

Greater bilgy

Greater bilby

Of course, you could say of Australia what someone once said of America and Britain: two nations divided by a common language. In the case of Oz you could also add ‘and by a ferociously competitive obsession with sport.’ So it’s wonderfully not home. Even Easter’s different in that here you get chocolate Easter bilbies rather than rabbits. Bilbies, by the way, are a sort of marsupial desert rat related to bandicoots. The lesser version died out in the 1950s so only the greater bilby is left (up to 20 inches long + tail half as long again) and you have to go to the arid deserts to find those. Not the choccy versions obviously: they don’t do too well in the deserts but they’re all over Melbourne:

Easter bilby

Easter bilby

shops full of ’em – and a lot bigger than the real thing. So, together with the egg avalanche, there’s no limit to the number of calories you can consume in celebrating the resurrection of Christ. Coupled with the glorious fact that there’s scarcely any mention of wretched soccer, all these novelties mean you’re never going to be lulled into thinking you’re still in dear old Blighty (or back in the old country as they delightfully put it here).

Hors D’Oeuvres

Even so there are some marked similarities to make you feel at home. One of the least striking is that most people are overweight. That is, I scarcely notice it, coming from what I regard as the global fat capital, i.e. Cambridge. The stats say that that’s not true, of course. The USA does these things better than the UK. Of course it does. But there’s not much in it. More than two-thirds of American adults are overweight and one person in three is obese. For the UK the prediction is that one in three will be obese by 2020. Currently in Australia 63% of the adult population is overweight, a figure that includes 28% who are obese.

The essential point is that there’s stuff all difference between those countries and the really critical thing is that the rates go on soaring. In the U.S. between 1980 and 2000 obesity rates doubled among adults and since 1980 the number of overweight adolescents has tripled. By 2025 one Australian child in three will be in the overweight/obese category.

Main course

The meat in this piece is provided by a report written by a bunch of Australian heavyweights – all Profs from Sydney or wherever. It has the droll title ‘No Time To Weight’ – do I need to explain that or shall I merely apologise for the syntax? ‘Oh c’mon!’ I hear our Aussie readers protest. ‘We’re going to hell in a handcart and you’re wittering about grammar. Typical b***** academic.’ Quite so. Priorities and all that. So the boffins’ idea is to wake everyone up to obesity and get policy-makers and parliamentarians to do something effective.No Time to Weight report

Why is this so important? Probably unnecessary to explain but obesity causes a variety of disorders (diabetes, heart disease, age-related degenerative disease, sleep apnea, gallstones, etc.) but in particular it’s linked to a range of cancers. Avid followers of this BbN blog will recall obesity cropping up umpteen times already in our cancer-themed story (Rasher Than I Thought?/Biting the bitter bullet/Wake up at the back/Twenty winks/Obesity and Cancer/Isn’t Science Wonderful? Obesity Talks to Cancer) and that’s because it significantly promotes cancers of the bowel, kidney, liver, esophagus, pancreas, endometrium, gallbladder, ovaries and breast. The estimate is that if we all had a body mass index (BMI) of less than 25 (the overweight threshold) there would be 12,000 fewer UK cancers per year. Mostly the evidence is of the smoking gun variety: overweight/obese people get these cancers a lot more often than lesser folk but in Obesity Talks to Cancer we looked at recent evidence of a molecular link between obesity and breast cancer.

Entrée (à la French cuisine not North American as in Main course)

Or, as you might say, a side dish of genetics. The obvious question about obesity is ‘What causes it?’ The answer is both complicated and simple. The complexity comes from the gradual accumulation of evidence that there is a substantial genetic (i.e. inherited) component. Many people will have heard of the hormone leptin, a critical regulator of energy balance and therefore of body weight. Mutations in the leptin gene that reduce the level of the hormone cause a constant desire to eat with the predictable consequence. But only a very small number of families have been found who carry leptin mutations and, although other mutations can drive carriers to overeating, they are even rarer.

However, aside from mutations, everyone’s DNA is subtly different (see Policing DNA) – about 1 in every 1000 of the units (bases) that make up our genetic code differs between individuals. All told the guess is that in  90% of the population this type of genetic variation can contribute to their being overweight/obese.

Things are made more complicated by the fact that diet can cause changes in the DNA of pregnant mothers (what’s called an epigenetic effect). In short, if a pregnant woman is obese, diabetic, or consumes too many calories, the obesity trait is passed to her offspring. This DNA ‘imprinting’ activates hormone signaling to increase hunger and inhibit satiety, thereby passing the problem on to the child.Preg Ob

So the genetics is quite complex. But what is simple is the fact that since 1985 the proportion of obese Australians has gone up by over 10-fold. That’s not due to genes misbehaving. As David Katz, the director of Yale University’s Prevention Research Center puts it: ‘What has changed while obesity has gone from rare to pandemic is not within, but all around us. We are drowning in calories engineered to be irresistible.’

Desserts

We might hope that everyone gets theirs but for obesity that’s not the way it works. The boffos’ report estimates that in 2008 obesity and all its works cost Australia a staggering $58.2 billion. Which means, of course, that every man, woman and child is paying a small fortune as the epidemic continues on its unchecked way. The report talks formulaically of promoting ‘Australia-wide action to harmonise and complement efforts in prevention’ and of supporting treatment. It’s also keen that Australia should follow the American Medical Association’s 2013 decision to class obesity as a disease, the idea being that this will help ‘reduce the stigma associated with obesity i.e. that it is not purely a lifestyle choice as a result of eating habits or levels of physical activity.’ Unfortunately this very p.c. stance ignores that fact that obesity is very largely the result of eating habits coupled to levels of physical activity. The best way to lose weight is to eat less, eat more wisely and exercise more.

In 2008 Australian government sources forked out $932.7 million over 9 years for preventative health initiatives, including obesity. This latest report represents another effort in this drive. Everyone should read it but, clear and well written though it is, it looks like a government report, runs to 34 pages and almost no one will give it the time of day.

The problem is that in Australia, as in the UK and the USA, all the well-intentioned propaganda simply isn’t working. As with tobacco, car seat belts and alcohol driving limits, the only solution is legislation, vastly unpopular though that always is – until most folk see sense. Start with the two most obvious targets: ban the sale of foods with excessive sugar levels (especially soft drinks) and make everyone have a BMI measurement at regular intervals, say biannually. Then fine anyone over 25 in successive tests who isn’t receiving some sort of medical treatment.

Amuse bouche

I know: I’ll never get in on that manifesto. But two cheers for ‘No Time To Weight’ and I trust the luminaries who complied it appreciate my puny helping hand from Cambridge. In the meantime, not anticipating any progress on a national front, I’m going to start my own campaign – it’s going to be a bit labour-intensive, one target at a time, but here goes!

The other evening I had dinner in a splendid Italian restaurant (The Yak in Melbourne: very good!). And delightful it would have been had I not shared with two local girls at the next table. One was your archetypal tall, slender, blonde, 25-ish Aussie female – the sort you almost feel could do with a square meal. Her companion of similar age was one of the dirigible models. (You’ll understand I wasn’t looking at them at all: I was with my life’s companion so no chance of that – but I do have very good peripheral vision. Comes from playing a lot of rugby). Each had one of the splendid pasta dishes on offer – but, bizarrely, they also ordered a very large bowl of chips. No prizes for guessing who ate all the fries. Miss Slim didn’t have one – not a single one! (OK, by now I was counting). Her outsize friend had the lot. How could she do that with a shining example of gastronomic sanity sitting opposite?

So c’mon Miss Aussie Airship: you know who you are. Let’s have no more of it. Obesity is not a personal ‘issue.’ Regardless of your calorie intake in one meal, your disgraceful behavior ruined a delightful dining experience for me, and quite possibly several other folk within eyeshot, upset the charming waitress and insulted The Yak’s excellent chef. Just think in future: there’s a place in life for chips – but it’s not with everything.

Reference

“Obesity: A National Epidemic and its Impact on Australia”

Twenty winks

Not now obviously but after you’ve read the first episode of this absorbing tale you may feel a nap is in order, despite the fact that in Wake up at the back we noted that snoring can give you cancer.

Setting aside that hazard, the general finding is that most people require seven or eight hours of sleep to function optimally. Fall short of that, to less than six hours even for one night, and we all know that the consequences may include a degree of grumpiness helped along by a tendency to clumsiness and generally heightened incompetence. If you happen to suffer from hypertension you could measure another result because your blood pressure will be even higher than usual for the rest of the day. However, these are all reversible states, so that real problems only come with more extended sleep deprivation and there is much evidence that this can profoundly affect memory, creativity and emotional stability, as well as leading to heart disease, diabetes and obesity. The molecular drive for the latter is that folk who are short of sleep have lower levels of the hormone leptin (which tells the brain you’ve had enough to eat) but higher levels of ghrelin (appetite stimulant). One week of only four hours nightly kip converts healthy young men to pre-diabetics in terms of their insulin and blood sugar levels.

The cancer link

To all of which must be added the dribble of reports over many years that disrupted sleep patterns, such as result from shift-work, may increase the risk of a variety of cancers (these include breast, prostate, bowel and endometrial cancers and also non-Hodgkin’s lymphoma). The effects are moderate (that is, the risk rise is small – typically up to 20%), making these findings suggestive rather than conclusive, although they are bolstered by a considerable number of studies on animals. So sleep, or rather lack of it, is yet another of these things that seems to affect cancer but for which really hard evidence is lacking. It’s not a9f5f190difficult to see why. You can’t put a number on ‘a good night’s sleep’ (though you can now get phone apps that record your every snort and contortion) nor do we understand the biological consequences of sleep disruption, and then there are the perpetual problems that everyone’s different and cancers take years to show themselves. However, you can put a figure on how you feel about sleep: our friends at the wonderful Karolinska Institute in Stockholm have come up with a Sleepiness Scale (1 = very alert, 9 = very sleepy, great effort to keep awake) – which could replace the traditional grunt when asked ‘How are you?’ ‘Oh, much as usual, about eight on the Karolinska Scale.’

Sleeping Off Breast Cancer

Trawling the literature it seems that the majority of cancer/sleep studies focus on the breast and a word about two of the most recent will suffice to paint the picture. In a large group of Japanese ladies over the age of 40 those who said they slept for less than six hours were markedly more likely to develop breast cancer than those who slept longer. Over nine hours a night (sleep that is) even appeared to give a degree of protection.

The main culprit for the breast cancer/sleep link is shift work, illustrated by the Danish military where women working night-shifts are more prone to breast cancer than those with normal sleep patterns and there is an upward trend in risk with years of night-shift work.

An association with ovarian cancer has also been reported although, somewhat perplexingly, that study didn’t show that the risk got bigger the longer night-shifts were worked. This rather confusing picture may reflect individual variation. As we all know, some folk are ‘larks’ – up at the crack of dawn – my lady wife is one – whereas others are ‘owls’ who perform better the later it is (no prize for guessing what kind of bird I am – bit of domestic incompatibility there!). It may be that ‘owls’ suffer less from night-shift perturbation and they may therefore be more likely to opt for that mode of work – and indeed the Danish study found that ‘larks’ on night-shifts were more likely to get breast cancer. As if that’s not enough, irregular shift patterns make it more difficult for women to conceive and working only nights increases the chances of miscarrying.

Similar results have been found for other cancers, notably of the bowel – 50% more likely to occur in those who sleep an average of less than six hours a night than those who zzzz for over seven. Put another way, the less than six hours risk is about the same as having a first degree relative with the disease or eating lots of red meat – and similar to that for breast cancer.

Mu Treadmill

th-2

th-1

Mice Sleep Too

It’s not a bad idea to keep in mind that we are very similar to mice – we’ve got more or less the same number of genes and exercising (on a treadmill for example) helps to keep at least some cancers at bay. Another similarity is that sleep deprivation upsets the works so that, for example, in models of colon cancer it reverses the beneficial effects of moderate exercise.

So insomnia is no laughing matter, however it comes about, and next time we’ll put two and two together by looking at the molecular story – after which you really may need forty winks.

 References

Kakizaki, M. et al. (2008).  Sleep duration and the risk of breast cancer: the Ohsaki Cohort Study. Br J Cancer  99, 1502–1505.

Hansen, J. and Lassen, C.F. (2012). Nested case-control study of night shift work and breast cancer risk among women in the Danish military. Occup Environ Med., 69, 551–556.

Bhatti, P. et al. (2012). Nightshift work and risk of ovarian cancer. Occup Environ Med., 0:1–7. doi:10.1136/oemed-2012-101146.

Thompson, C.L. et al. (2011). Short Duration of Sleep Increases Risk of Colorectal Adenoma. Cancer 117, 841–847.

Zielinski, M.R. et al. (2012). Influence of chronic moderate sleep restriction and exercise on inflammation and carcinogenesis in mice. Brain, Behavior, and Immunity 26, 672–679.

Pig’s ’ere – and far from a bore

First love

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

Sequencing Sus scrofa

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

1.11807_Pig1_cutout

Almost like a pig

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

Them and us

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

Model humans

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

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

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

Reference

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

Wake up at the back

Living with someone of the opposite sex, or getting married as it used to be known, is an interesting experience. One of the things you rapidly discover that your Mum never warned you about is that women are a distinct species.  You missed that revelation in your biology classes? Serves you right for snoozing on the back row but, as a recap of the evidence, consider the following. Species often show major differences in sensory perception – thus our cat is much better than I am at seeing in the dark, though he misses out a bit in daylight as cats don’t have colour vision. When it comes to hearing it’s a bit the other way round: most of the time you can shout at him til you’re hoarse with absolutely no effect – but one faint clink of a food bowl at the back door and, yet again, he’ll set a new Feline Fifty metres Steeplechase record from the front garden. And dogs, as is well known, hear frequencies way beyond what we can pick up.

Not in my lectures!!

The gentle sex has similarly evolved beyond what mere man can manage. Take colour, for example, at which men are, as we’ve noted, quite good – compared to cats. But, as you discover the first time you are taken ‘clothes shopping’ by your wife, other half, inamorata, partner, mistress or whatever, women have evolved far beyond merely spotting that blue is different from red and being able to recite Richard Of York (to remind themselves of the rainbow sequence). They see ‘combinations’ – so you are curtly informed that what has taken your fancy ‘just doesn’t go together’ in the sort of voice that adds ‘any nitwit can see that’ without the need to expend breath on the last seven syllables.

They’re at a similarly lofty level of evolution when it comes to sound. My lady wife avers that I snore – all the time (when asleep, that is) and very loudly. So much so that she tends to use a bed at the opposite end of the house for sleeping and only ventures within sonar range for other purposes. I’d always explained this behaviour as a manifestation of the amazing imagination possessed of the female that us boys are, of course, completely lacking. However, I’ve now come to appreciate that, like Fido (who sleeps in the kitchen), she simply has exquisitely sensitive aural apparatus. So maybe I do snore – but only very quietly or at ultra high frequency, so that I would be undetectable at rest to my own species and only my beloved and the dog would know what was going on (oh, and the cat because he can see the heaving chest).

Which is very reassuring since some fellows at the Universities of Wisconsin and Barcelona have got together to discover that snoring makes you nearly five times more likely to develop cancer. Strictly the problem is sleep disordered breathing (SDB) – which happens when there’s some kind of blockage of the upper airway and, apart from disrupting sleep, it can make you snore. Of course, there’s evidence that sleep disruption can contribute to all sorts of problems from heart disease to car crashes but this is the first study making a link to cancer.

No problem for me (discounting the wife’s super sonar) but should real, habitual snorers panic? Please don’t for most of the usual reservations to this type of study apply – relatively small numbers (1522) for example. The volunteers came from an alluringly named body of men and women called the Wisconsin Sleep Cohort, set up in 1988 for prospective studies of sleep disorders. In fact the interesting ones here are what we might call the Winsomniacs – the 365 of the Cohort who can’t do it rather than the majority of Badger State dreamers. Split in this case into sub-groups of SDB severity – the strongest association being with the most severe SDB. Although the authors did their best to allow for other factors (obesity – a common cause of SDB – diabetes, smoking, etc.) it’s almost impossible in this type of study to eliminate everything bar the one factor you’re focussing on.

The most frequent linked cancer was of the lung, followed by bowel, ovary, endometrial, brain, breast, bladder, and liver. And the cancer risk was up to four-fold greater for the worst afflicted.

Do the boffins have any helpful suggestions? Not really. Those unlucky enough to be severely affected can try a gadget called a continuous positive airway pressure device but, for the rest, console yourselves that the risk is small and the data so far are very preliminary. Put another way, you have more important things to think about – like finding a partner (preferably with sub-standard sonar detection capability) who loves you so much they’re willing to poke you in the ribs whenever you become aurally intrusive.

References

http://www.telegraph.co.uk/health/healthnews/9278214/Snoring-can-raise-cancer-risk-five-fold.html

Javier Nieto, F.J. et al. (2012). Sleep-disordered Breathing and Cancer Mortality: Results from the Wisconsin Sleep Cohort Study. American Journal of Respiratory and Critical Care Medicine 186, Iss. 2, pp 190–194.