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.

raleighs_first_pipe_in_england-jpeg

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!

References

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.

Holiday Reading (2) – Poking the Blancmange

An evolutionary hiccup

It’s well known that tracing our family tree back 400 million years reveals a fishy past. This history is enshrined in our DNA in the pattern of nerves that control breathing. From time to time that control throws a wobbly in the form of involuntary spasms of the diaphragm manifested as a fit of hiccups – what the medics call singultus, which in Latin means sobbing – readily brought on by contemplating a comprehensive map of intracellular signalling pathways. Hiccups, however, are caused, as Neil Shubin, in his wonderful book Your Inner Fish has explained, by a mis-firing neuron in our brain stems that produces the type of electric signals that control the regular motion of amphibian gills. A genetic recipe hoarded in the nuclear loft is inadvertently recalled. For the most part this result of DIY evolution is no more than mildly embarrassing, although the poor fellow who made the Guinness Book of Records by hiccupping for 68 years may have used a stronger term.

As we’re really talking about cancer, we should mention that persistent spasms of hiccups and difficultly swallowing may be indicators of esophageal cancer, where a tumour in the gullet (the tube connecting the back of the mouth to the stomach) grows into the trachea and flips the hiccup switch by mechanical pressure.

Je pense, donc je suis un blanc-manger

Whilst the key feature of all these pathways is that they connect the outside world to the nucleus of a cell, it’s become clear that each pathway does not exist in isolation. Individual pathways can talk to each other – sometimes called cross-talk – individual domino runs intersecting, if you like. So evolution has cooked up thousands of proteins floating around in our cells that can be mapped into discrete signal pathways but, in the molecular jostle of the cell, each may affect any of the others – if not directly then via just a few intermediates. To avoid the Tokyo subway syndrome it’s easiest to think of the cell as a blancmange: poke it anywhere and the whole thing wobbles.

NetworkBlancmange

The complex network of signalling pathways in cells.

Left: the dots represent proteins that inter-communicate (lines) – best thought of as a blancmange.

Why is grasping this picture of what seems like a molecular madhouse important? Well, one thing we should bear in mind is that the set-up may look chaotic to us but our cells somehow make perfect sense of it all because they take clear decisions as to what to do. But the reason for grappling with it at all, other than to be humbled by our ignorance, is that these signal systems are a major target for anti-cancer drugs. To be more precise, it’s disruptions in these proliferation-controlling pathways, caused by mutations, at which we take aim with the contents of our drug cocktail cabinet.

What goes wrong in cancer?

If you want a three word definition of cancer ‘cells behaving badly’ will do fine. If you insist on being scientific ‘abnormal cell proliferation’ covers it nicely, meaning that control of cell replication has been overcome to the extent that cells reproduce more rapidly than they should or at an inappropriate time or in the wrong place. Underlying this abnormal behaviour is damage to DNA, that is, mutations. This remains true even if the initial cause does not directly affect DNA. It’s estimated that about 20% of the global cancer burden comes from infections, mainly in contaminated drinking water. These can cause chronic inflammation that eventually leads to mutations and thence to cancer. Other factors, for example, tobacco smoke and radiation, can directly damage DNA and about 10% of cancers are set off by what you might call a taxing inheritance – mutations already present in DNA at birth.

The capacity for high-throughput sequencing of complete human genomes has spawned ambitious projects that include Genomics England’s sequencing of 100,000 genomes by 2017 and The Cancer Genome Atlas that aims to provide a mutation data base for all the major cancers. One of the most mind-boggling facts that has already emerged from this revolution is the extent of disruption that can occur in the genomes of cancer cells: as many as one hundred thousand mutations within one cell. For the sake of completeness we should note that, cancer being cancer, the mutational spectrum is astonishing and, at the other end of the scale, there’s a childhood leukemia that results from just one change to DNA and there’s a type of central nervous system tumour that appears to develop without any mutations at all. For the most part, however, cancer cells carry a mind-boggling number of mutations and the assumption, nay hope, is that the vast majority of these changes are ‘passenger’ mutations that do not affect cellular behaviour: they’re a by-product of the genetic mayhem characterizing cancer cells. The ones that count are ‘driver’ mutations that can arise in any of several hundred of our 20,000 or so genes, changing the activity of the proteins they encode to contribute to cancer development. Only a small number (half a dozen or so), of these drivers, acting together, is required for cancer to emerge. Thus, although only a relatively small group of ‘drivers’ is needed, almost limitless combinations can arise.

The accumulation of mutations takes time, which is why cancers are largely diseases of old age: two thirds of them only appear in people over the age of sixty. The estimate is that if we lived to 140 everyone would get cancer but, pending that happy day, when or whether the disease manifests itself in an individual is indeed a matter of genetic roulette – genetic evolution within cancer cells. So wonderful has the technology become we can now inspect individual cells in tumours to reveal that driver mutations occur in single cells that can expand to form groups of cells, called clones. These multiple clones can modulate their mutational profile independently and, as a result, proliferate at different rates. So you can picture tumours as a complex patchwork of genetically related, competing clones. In other words, as we’ve suspected all along, cancers are a form of dynamic Darwinism.

The critical point is that key mutations drive cancer and they do so by upsetting the normal working of signal pathways that control whether cells proliferate or not. You could say it’s Nature poking the blancmange but these are delicately selected pokes – the product of the evolution of a cancer’s genetic signature – that just tweak signalling mechanisms enough to make cells a little more likely to multiply. In coming up with drugs that target specific mutations we’re giving the blancmange another poke – the aim being, of course, to prod it back to normality.

An obvious question

Having mentioned that, albeit very rarely, cancers emerge that don’t seem to be driven by changes in the sequence of DNA – how do they do that? The answer lies in epigenetic modifications – any modification of DNA, other than in the sequence of bases, that affects how an organism develops or functions. They’re brought about by tacking small chemical 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. In effect this makes the DNA more difficult to get at for the molecular machines that turn the information in genes into proteins. So these small chemical additions act as a kind of ‘super switch’ that can, for example, block genes that act as brakes on cell proliferation – hence promoting cancer.

Reference

Neil Shubin Your Inner Fish, Random House, 2008.

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 more winks

In Episode One we alerted ourselves to the large amount of evidence saying that a good night’s sleep really is essential if you wish to reduce your chances of a wide variety of medical misfortunes. But what do we know about how molecules respond to sleep disruption to produce such nasty effects?

Molecular Clocks

Life on earth depends on energy sent forth by the sun and, in synchrony with the rotation of our planet, many of the inner workings of mammals fluctuate over each period of roughly 24 hours. This pattern is called the circadian clock, its most obvious manifestation being the sleep-wake cycle. Over the years considerable evidence has accumulated that the link between shift-work and cancer is probably due to circadian rhythm disruption and suppression of nocturnal production of a hormone called melatonin. All living things make melatonin (in mammals in the pineal gland of the brain) and it signals through a variety of protein receptors on cells to regulate the sleep-wake cycle but it also plays a role in protecting DNA from damage.

Melatonin production is regulated by the circadian oscillator, itself controlled by two sets of proteins that control each other’s expression in a feedback loop. Thus one pair, CLOCK and BMAL1, activates Cryptochrome and Period. They in turn repress CLOCK and BMAL1 – the upshot being that the activities of both pairs oscillate over a day-night cycle: as one goes up the other comes down. These central regulators are encoded by evolutionarily ancient genes (two for Cryptochromes and three for Period proteins). In plants and insects CRY1 responds to light but in mammals CRY1 and CRY2 work independently of light to inhibit BMAL1-CLOCK.

Two interlocked feedback loops control clock protein expression

CRY-CLOCK

OUTCOME: ≈ 24 hour cycle expression of PER & CRY

BMAL1 & CLOCK 12 hours out of phase

Alarming the Clock

So having sounded the alarm that just one night’s sleep shortage has obvious effects, what do the genes make of it? Well, the short answer is they get upset. A recent study took blood samples from a group of normal people and found that more than 700 genes (about 3% of our total number) significantly changed their level of expression over 1 week of insufficient sleep (5.7 h) by comparison with 1 week of sufficient sleep (8.5 h). About two-thirds were reduced whilst one-third was up-regulated (made more of their protein product). Unsurprisingly, among those that went down were the major clock regulators. It’s worth noting that the sleep perturbation in this experiment was relatively mild – intended to be similar to that experienced by many individuals. The genes most strongly affected play roles in a wide range of biological processes – DNA structure (hence gene expression), metabolism, stress responses and inflammation. The responses of genes to changes in sleep patterns are not the result of mutation (i.e. changes in the sequence of DNA)  but, at least in part, they’re caused by small changes in the structure of DNA. {These are epigenetic modifications – any modification of DNA, other than in the sequence of bases, that affects how an organism develops or functions. They’re brought about by tacking small chemical 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}. Thus there is evidence for gene silencing by hyper-methylation of CRY2 (adding methyl groups (CH3) to its DNA) and the converse effect of hypo-methylation (removing methyl groups) of CLOCK occurs in women engaged in long-term shift work and is associated with an increased risk of breast cancer.

Inflaming the Problem

The cells that mediate inflammation and immune responses also have circadian clocks – meaning that normally these processes are rhythmically controlled and clock disruption (for example by sleep loss) affects this pattern. Disabling the clock in mice (by knocking out CRY altogether) switches on the release of pro-inflammatory messengers and knocking out one of the Period genes (PER2) makes mice cancer-prone – reflecting the fact that MYC (the key proliferation driver) is directly controlled by circadian regulators and is consistently elevated in the absence of PER2.

Clock Faces

The mass that comprises a tumour is a mixture of cells – cancer cells and normal cells attracted to the locale – so it’s a quite abnormal environment and in particular there may be regions where the supply of oxygen and nutrients is limited. This is sensed as a stress by the cells, one response being to lower protein production until normal conditions are restored. If this doesn’t happen within a given time the response switches to one leading to cell suicide. One way in which overall protein output can be reduced is by activating an enzyme (IRE1α) that breaks down code-carrying messenger RNAs that direct assembly of new proteins. Remarkably, it has emerged that one of the mRNAs targetted by IRE1α is the core circadian clock gene, PER1. The degradation of PER1 mRNA means that less PER1 protein is made, which in turn disrupts the clock. However, it seems that PER1 has other roles that include helping the cell suicide response – a major anti-cancer defence. All of which suggests that disruption of the IRE1α/ PER1 balance might have serious consequences. Indeed IRE1α mutations have been found in a variety of cancers including brain tumours in which low levels of PER1 are an indicator of poor prognosis. The IRE1α mechanism coincidentally activates the transcription factor XBP1 (as well as PER1 mRNA decay) and one target of XBP1 is the gene encoding a messenger (CXCL3) that makes blood vessels sprout offshoots. Thus this master regulator suppresses cell death, activates proliferation (lowering PER1 deregulates MYC) and promotes new blood vessel formation.

A Tip for Snoozing

If you’re still wide awake it just goes to prove the utter fascination of biology – but today’s story says that you have to find ways of, if not falling asleep, at least courting insensibility (as Christopher Fry put it). If it’s a real problem for you may I make a really radical suggestion? Turn to our physicist friends and select from their recent literary avalanche. A ‘brief history of …’ something or other will do fine. It’s a knock-out! Sweet dreams!!

References

Möller-Levet, C.S., Archer, S.N., Bucca, G., Laing, E.E., Slak, A., Kabiljo, R., Lo, J.C.Y., Santhi, N., von Schantz, M., Smith, C.P. and Dijk, D.-J. (2013). Effects of insufficient sleep on circadian rhythmicity and expression amplitude of the human blood transcriptome. PNAS 110, E1132-E1141.

Fu, L.N. et al. (2002). The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Cell 111, 41-50.

Zhu, Y. et al. (2011). Epigenetic impact of long-term shiftwork: pilot evidence from circadian genes and whole-genome methylation analysis. Chronobiol Int, 28, 852–861.

Pluquet, O. et al. (2013). Posttranscriptional Regulation of PER1 Underlies the Oncogenic Function of IREα. Cancer Res., 73, 4732-4743.