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.

 

Advertisements

Pass the Aspirin

And so you should if you’ve got a headache – unless, of course, you prefer paracetamol. There can scarcely be anyone who hasn’t resorted to a dose of slightly modified salicylic acid (For the chemists: its hydroxyl group is converted into an ester group (R-OH → R-OCOCH3) in aspirin), given that the world gobbles up an estimated 40,000 tonnes of the stuff every year. It’s arguable, therefore, that an obscure clergyman by the name of Edward Stone has done more for human suffering than pretty well anyone, for it was he who, in 1763, made a powder from the bark of willow trees and discovered its wondrous property. The bark and leaves had actually been used for centuries – back at least to the time of Hippocrates – for reducing pain and fever, although it wasn’t until 1899 that Aspirin made its debut on the market and it was 1971 before John Vane discovered how it actually worked. He got a Nobel Prize for showing that it blocks production of things called prostaglandins that act a bit like hormones to regulate inflammation (for the chemists – again! – it irreversibly inactivates the enzyme cyclooxygenase, known as COX to its pals).

Daily pill popping

Aside from fixing the odd ache, over the years evidence has gradually accumulated that people at high risk of heart attack and those who have survived a heart attack should take a low-dose of aspirin every day. In addition to decreasing inflammation (by blocking prostaglandins) aspirin inhibits the formation of blood clots – so helping to prevent heart attack and stroke. Almost as a side-effect the studies that have lead to this being a firm recommendation have also shown that aspirin may reduce the risk of cancers, particularly of the bowel (colorectal cancer). Notably, Peter Rothwell and colleagues from Oxford showed that daily aspirin taken for 10 years reduced the risk of bowel cancer by 24% and also protected against oesophageal cancer – and a more recent analysis has broadly supported these findings. In addition they have also found that aspirin lowers the risk of cancers spreading around the body, i.e. forming distant metastases.

Why is aspirin giving us a headache – again?

First because a large amount of media coverage has been given to a report from Leiden University Medical Center, presented at The European Cancer Congress in September, that used Dutch records to see whether taking aspirin after being diagnosed with gastrointestinal cancer influenced survival. Their conclusion was that patients using aspirin after diagnosis doubled their survival chances compared with those who did not take aspirin. Needless to say, these words have been trumpeted by newspapers from The Times to the Daily Mail in the usual fashion (“Aspirin could almost double your chance of surviving cancer”). Unfortunately we can’t lay all the blame on the press: the authors of the report used the tactic of issuing a Press Release, a thoroughly reprehensible ploy for gaining attention when the work involved has not been peer reviewed. (The point here for non-scientists is that you can stand up at a meeting and say the moon’s made of blue cheese and it’s fine. Only after your work has been assessed by colleagues in the course of the normal publication process does it begin to have some credibility). So there’s a problem here, with what was an ‘observational study’, as to just what the findings mean – and the wise thing is to wait for the results of a ‘randomised controlled trial’ that is under way. 

The second source of mental strain is down to the ferociously named United States Preventive Services Task Force that has just (September 2015) come up with the recommendation that we should take aspirin to prevent bowel cancer. Why should we pay any attention? Because the ‘Force’ are appointed by the US Department of Health and they wield great influence upon medical practice – and because it’s the first time a major American medical organization has issued a broad recommendation to take aspirin to prevent a form of cancer.

In this latest oeuvre they confirm that the well-known risks attached to aspirin-eating (ulcers and stomach bleeding) are out-weighed by the protection against heart disease in those between the ages of 50 and 69 who are at high risk (e.g., have a history of heart attacks). If you feel your heart can take the strain you can find out your risk by using the National Heart, Lung, and Blood Institute’s online risk assessment tool. To get an answer you need to know your age, sex (i.e. gender, as its called these days), cholesterol levels (total and high density lipoproteins, HDLs – they’re the ‘good’ cholesterol), whether you smoke and your systolic blood pressure (that’s the X in X/Y).

This is such a critical issue it’s worth seeing what the Task Force actually said: “The USPSTF recommends low-dose aspirin use for the primary prevention of cardiovascular disease (CVD) and colorectal cancer in adults ages 50 to 59 years who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years.”

If you’re younger than 50 or over 70 you’re on your own: the Force doesn’t recommend anything. And if you’re 60 to 69 the wording of their advice is wonderfully delicate: The decision to use low-dose aspirin to prevent CVD (cardiovascular disease) and colorectal cancer in adults ages 60 to 69 years who have a greater than 10% 10-year CVD risk should be an individual one.”

So that’s cleared that up …

Er, not quite. Various luminaries have been quick to demur. For example, Dr. Steven Nissen, the chairman of cardiology at the Cleveland Clinic has opined that the Task Force “has gotten it wrong.” In other words aspirin does more harm than good – though he might be a bit late as seemingly an astonishing 40% of Americans over the age of 50 take aspirin to prevent cardiovascular disease. I reckon that’s about 40 million people. Mmm … so that’s where the 40,000 tonnes goes (well, about one-fifth of it).

What’s the advice?

We’re more or less where we came in. I take an aspirin, or more usually a paracetamol, when I’ve got a stonking headache. Otherwise I wouldn’t take any kind of pill or supplement unless there is an overwhelming medical case for so doing. And pill-poppers out there might note the findings of Eva Saedder and her pals at Aarhus University that the single, strongest independent risk factor for drug-induced serious adverse events is the number of drugs that the patient is taking.

References

Rothwell, P. et al. (2012). Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials, Lancet DOI:1016/S0140-6736(11)61720-0

Rothwell P. et al. (2012). Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trial, Lancet DOI:1016/S0140-6736(12)60209-8

Lancet editorial on Rothwell et al. 2011.

Algra, A. and Rothwell, P. (2012). Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials, Lancet Oncology DOI:10.1016/S1470-2045(12)70112-2.

Frouws M et al. Aspirin and gastro intestinal malignancies; improved survival not only in colorectal cancer? Conference abstract. European Cancer Congress 2015

Press release: Post diagnosis aspirin improves survival in all gastrointestinal cancers. The European Cancer Congress 2015. September 23 2015

Cuzick J, Thorat MA, Bosetti C, et al. Estimates of benefits and harms of prophylactic use of aspirin in the general population. Annals of Oncology. Published online August 5 2014

U.S. Preventive Services Task Force Draft Recommendation Statement: Aspirin to Prevent Cardiovascular Disease and Cancer

Saedder, E.A. et al. (2015). Number of drugs most frequently found to be independent risk factors for serious adverse reactions: a systematic literature review. British Journal of Clinical Pharmacology 80, 808–817.