Going With The Flow

The next time you happen to be in Paris and have a spare moment you might wander over to, or even up, the Eiffel Tower. The exercise will do you good, assuming you don’t have a heart attack, and you can extend your knowledge of science by scanning the names of 72 French scientists that you’ll find beneath the square thing that looks like a 1st floor balcony. Chances are you won’t recognize any of them: they really are History Boys – only two were still alive when Gustave Eiffel’s exhibit was opened for the 1889 World’s Fair.

One of the army of unknowns is a certain Michel Eugène Chevreul – and he’s a notable unknown in that he gave us the name of what is today perhaps the most familiar biological chemical – after DNA, of course. Although Chevreul came up with the name (in 1815) it was another Frenchman, François Poulletier de la Salle who, in 1769, first extracted the stuff from gallstones.

A few clues

The ‘stuff’ has turned out to be essential for all animal life. It’s present in most of the foods we eat (apart from fruit and nuts) and it’s so important that we actually make about one gram of it every day to keep up our total of some 35 grams – mostly to be found in cell membranes and particularly in the plasma membrane, the outer envelope that forms the boundary of each cell. The cell membrane protects the cell from the outside world but it also has to allow chemicals to get in and out and to permit receptor proteins to transmit signals across the barrier. For this it needs to be flexible – which why membranes are formed from two layers of lipids back-to-back. The lipid molecules have two bits: a head that likes to be in contact with water (blue blobs in picture) to which is attached two ‘tails’ ­– fatty acid chains (fatty acids are unbranched chains of carbon atoms with a methyl group (CH3–) at one end and a carboxyl group (–COOH) at the other).

Bilayer

Cholesterol_molecule_ball

A lipid bilayer                                          

De la Salle’s substance

 

The lipid ‘tails’ can waggle around, giving the plasma membrane its fluid nature and, to balance this, membranes contain roughly one molecule of ‘stuff’ for every lipid (the yellow strands in the lipid bilayer). As you can see from the model of the substance found by de la Salle, it has four carbon rings with a short, fatty acid-like tail (the red blob is an oxygen atom). This enables it to slot in between the lipid tails, strengthening the plasma membrane by making it a bit more rigid, so it’s harder for small molecules to get across unless there is a specific protein carrier.

Bilayer aThe plasma membrane. A fluid bilayer made of phospholipids and cholesterol permits proteins to diffuse within the membrane and allows flexibility in their 3D structures so that they can transport small molecules and respond to extracellular signals.


De la Salle’s ‘stuff’ has become famous because high levels have been associated with heart disease and much effort has gone into producing and promoting drugs that reduce its level in the blood. This despite the fact that numerous studies have shown that lowering the amount of ‘stuff’ in our blood has little effect on mortality. In fact, if you want to avoid cardiovascular problems it’s clear your best bet is to eat a Mediterranean diet (mostly plant-based foods) that will make no impact on your circulating levels of ‘stuff’.

By now you will have worked out that the name Chevreul came up with all those years ago is cholesterol and it will probably have occurred to you that it’s pretty obvious that our efforts to tinker with it are doomed to failure.

We’ve known for along time that if you eat lots of cholesterol it doesn’t make much difference to how much there is in your bloodstream – mainly because cholesterol in foods is poorly absorbed. What’s more, because it’s so important, any changes we try to make in cholesterol levels are compensated for by alterations the internal production system.

Given how important it is and the fact that we both eat and make cholesterol, it’s not surprising that quite complicated systems have evolved for carting it around the body and delivering it to the right places. These involve what you might think of as molecular container ships: called lipoproteins they are large complexes of lipids (including cholesterol) held together by proteins. The cholesterol they carry comes in two forms: cholesterol itself and cholesterol esters formed by adding a fatty acid chain to one end of the molecule – which makes them less soluble in water.

lipoprotein-structureChol est fig

Lipoprotein                                                               Cholesterol ester

Formed by an enzyme – ACAT –
adding a fatty acid to cholesterol.
Avasimibe blocks this step.

 

So famous has cholesterol become even its taxi service has passed into common language – almost everyone knows that high-density lipoproteins (HDLs) carry so-called ‘good cholesterol’ (back to the liver for catabolism) – low concentrations of these are associated with a higher risk of atherosclerosis. On the other hand, high concentrations of low-density lipoproteins (LDLs) go with increasing severity of cardiovascular disease – so LDLs are ‘bad cholesterol’.

What’s this got to do with cancer?

The evidence that cholesterol levels play a role in cancer is conflicting. A number of studies report an association between raised blood cholesterol level and various types of cancer, whilst others indicate no association or the converse – that low cholesterol levels are linked to cancers. However, the Cancer Genome Atlas (TCGA) that profiles DNA mutations and protein expression reveals that the activity of some genes involved in cholesterol synthesis reflect patient survival for some cancer types: increased cholesterol synthesis correlating with decreased survival. Perhaps that accounts for evidence that the class of cholesterol lowering drugs called statins can have anti-tumour effects.

In a recent development Wei Yang and colleagues from various centres in China have come up with a trick that links cholesterol metabolism to cancer immunotherapy. They used a drug (avasimibe) that blocks the activity of the enzyme that converts cholesterol to cholesterol ester (that’s acetyl-CoA acetyltransferase – ACAT1). The effect of the drug is to raise cholesterol levels in cell membranes, in particular, in killer T cells. As we’ve noted, this will make the membranes a bit more rigid and a side-effect of that is to drive T cell receptors into clusters.

One or two other things happen but the upshot is that the killer T cells interact more effectively with target tumour cells and toxin release by the T cells – and hence tumour cell killing – is more efficient. The anti-cancer immune response has been boosted.

Remarkably, it turned out that when mice were genetically modified so that their T cells lacked ACAT1, a subset of these cells (CD8+) up-regulated their cholesterol synthesis machinery. Whilst this seems a paradoxical response, it’s very handy because it is these CD8+ cells that kill tumour cells. Avasimibe has been shown to be safe for short-term use in humans but the genetic engineering experiments in mice suggest that a similar approach, knocking out ACAT1, could be used in human immunotherapy.

References

Yang, W. et al. (2016). Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism. Nature 531, 651–655.

Dustin, M.L. (2016). Cancer immunotherapy: Killers on sterols. Nature 531, 583–584.

 

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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”