Tag Archives: cancer

old age and malbec

Dorothy was born in 1911. She is 102. When someone over 100 is admitted to our ward there is always a lot of interest – but it is happening more and more. Dorothy, or Dot, as she is known by her friends, has been living on her own in sheltered housing. She has her own ground floor flat, but eats meals with the other elderly residents and has help with washing and dressing in the morning, and there is always a manager on hand if there are problems. Slide1She can make herself simple meals and cups of tea, and her 78 year-old son, David, usually visits every Sunday.  I saw her in our ward last week. She had fallen over on Sunday night and bashed her head on the edge of a table, resulting in a huge bruise over her right eye. She has atrial fibrillation and is on warfarin – the ambulance crew brought her in to hospital as she was a bit confused and they were worried she might have a blood clot on her brain.

The CT head scan on the left of a healthy 96 year old woman, the one on the right is of a 23 year old woman. The dark portion in the middle of the old brain is fluid, not brain. The younger person's head is completely full of brain.
The CT head scan on the left is that of a healthy 96 year old woman, the one on the right is that of a 23 year old woman. The dark portion in the middle of the old brain is fluid, not brain. The younger person’s head is completely full of brain.

Luckily the CT scan of her head showed no evidence of serious bleeding, although her brain was considerably shrunken compared to a young person. She was quite deaf, but clearly had most of her marbles. She recounted how her father had fought, and was wounded, in the Battle of the Somme in the first world war, and her husband Rodney, who died in 1980 had fought in the second. She worked in a munitions factory during the war and had three children – all boys. It’s strange calling elderly people children, but offspring or any other word does not seem quite right. Only the youngest was still alive. She could remember the names of all 5 grandchildren and 7 great-grandchildren, but did struggle with the name of the Prime Minister and what year it was. Her brain was old as well as her skin and her ears, and all the rest of her.

How much longer will Dot live? There was an entertaining paper in the Christmas BMJ in 2011. http://www.bmj.com/content/343/bmj.d7679

It has been shown that for any cohort of elderly people, the main determinant of longevity is how old you are – as we get older the more likely we are to die sooner. The second most important factor is gender – women live longer than men. The third, somewhat surprisingly, is how fast you can walk. This is probably because being able to walk fast requires a lot of things to be working well – good lungs, good cardiac function, good muscles, good joints, good brain function, good eyesight, good peripheral nerve function etc. The paper suggests another alternative explanation – that if you walk slowly the grim reaper will catch up with you.

One explanation of why elderly people die soon if they cannot walk fast. Illustration by Belle Mellor - http://bellemellor.com (with permission - thanks Belle)
One explanation of why elderly people die soon if they cannot walk fast. Illustration by Belle Mellor – http://bellemellor.com
(with permission – thanks Belle)

Why do people get old? This is a difficult question, and I cannot give you a definite answer, but will give you my thoughts.  Ageing (aging in the US) seems inevitable.  We can guess how old someone is by their skin, which becomes wrinkled – their hair becomes thin and grey, and their posture becomes bent. The cells in our skin, bones, brain and just about everywhere else continually become older, but some of our cells do not age in the same way. Think about a sixty year old man who becomes a new father.  His sperm have contributed to make a baby that is not old, but brand new. The cells in his testes which have made the sperm are old, but they must have in them the information about how to make a cell which is not old. This, to me, very much suggests that old cells have not lost the information in the form of DNA sequence that they had when they were new. The creation of Dolly the sheep confirms this. Dolly was made from the nucleus of  her “mother’s” mammary gland cell (she was called Dolly after Dolly Parton, who has very impressive mammary glands). In a test-tube this nucleus was inserted into an egg cell of another sheep (also her mother?) and processed to de-differentiate it.

Dolly Parton - from Wikimedia commons
Dolly Parton – from Wikimedia commons

This means the nucleus of the mammary gland cell was changed so that instead of only being able to make more, old, mammary gland cells, it could make all the new and different cells of baby Dolly the sheep. So, I’ll ask the question again, why do cells get old? It’s not that they have lost the information about how to be new cells, but nature has determined that after a certain period of time they change into old cells. What is happening in the cells to make them old? – clearly they are not so damaged that the DNA sequence is irreparably altered. There must be a clock inside cells that tells them how old they are – this is suggested by the classic studies of Leonard Hayflick, who showed that cells from human babies only divide about 50 times, and then stop.

cells must have some sort of clock inside them - it may well be the amount of methylation of DNA in the nucleus
cells must have some sort of clock inside them – it may well be the amount of methylation of DNA in the nucleus

Cells from older people divide far fewer times. It was thought for many years that the reason cells could only divide a certain number of times was because each time division took place, the teleomeres at the end of each chromosome become shorter. When they become too short, the cell can no longer divide. Teleomeres have been likened to like the plastic bits at the end of shoelaces – they stop the lace from fraying and are necessary in chromosomes to keep the DNA strands from coming apart.

It may well be that short teleomeres contribute to the cellular clock, but it seems they are not the only answer.

teleomeres are on the end of chromosomes like the bits of plastic on the end of shoelaces - to stop them fraying
teleomeres are on the end of chromosomes like the bits of plastic on the end of shoelaces – to stop them fraying

More recent research suggests that epigenetic changes in DNA may be responsible. Epigenetics is a very fashionable science. Once a cell is differentiated in the growing embryo – say into a skin cell – its DNA becomes progressively altered. In particular methyl groups (CH3) become attached to a cytosine nucleotide when a cytosine and guanine are next to each other in the nucleic acid chain (CpG). This methyl group attached to the cytosine is copied when the cell divides. Recent research suggests that the age of cells is closely related to the number of methyl groups attached to CpG sequences in DNA.

http://genomebiology.com/2013/14/10/r115

What to me is really interesting, is that when sperm cells meet egg cells and their nuclei fuse to make the start of a new baby, all the methyl groups are stripped from the CpG sequences in DNA.  This looks like a definite candidate for the cellular clock.

But why do we need to age? What if cells stayed “new”? What if we could stop the cellular clock? If we could inject a substance into Dot which reversed the epigenetic changes would she suddenly get lovely wrinkle-free baby-like skin and a fully functioning brain, ears and eyes? I don’t know, but I suspect not – answers please.

Why did evolution invent a clock in our cells to stop them dividing as we get older? One explanation for this is that cells become damaged with time, and dividing may not be a good thing for damaged cells as it is more likely that they will become malignant. We now know that most malignant cells develop a sequence of gene defects over time, which when added together cause the cell to become cancerous. Maybe the clock, which limits the number of divisions, is a way of preventing further DNA damage and malignancy. Certainly it seems that reactive oxygen compounds that can cause damage to DNA also cause CpG methylation – in a way causing premature ageing of cells.

I used to think that the reason our cells got older was so that we would die and no longer be competition for our children, who, through evolution, had become more fit than us.  It seems this is not the explanation because there is very good evidence that early humans did not die from age-related causes, but from infections and trauma.  The average life-span in prehistoric times was much lower than in modern times, most people dying before 30 and nearly all before 40 years of age.  This means that it is not possible for evolution to select for, or against, those people who lived longer, because there were so few of them. Instead it seems that evolution only cares about keeping us alive until we have produced and reared babies – after that it has no interest or influence one way or the other. If there was a new gene that made a prehistoric human live longer, it would be extremely unlikely that the owner would survive longer and there would be no positive or negative pressure to keep it. This does not mean that our genes cannot influence how long we live. An important factor in determining how long we live is how long our parents lived. Another is where we live and our lifestyle.

Roger Corder, scientist and author of The Red Wine Diet
Roger Corder, scientist and author of The Red Wine Diet

There is a wonderful book by an erstwhile colleague of mine, Roger Corder, called The Red Wine Diet, which suggests that eating foods with certain polyphenols can make us live longer.

polyphenols are large molecules made up of lots of phenols - they are useful antioxidants which trap oxygen radicals
polyphenols such as tannins are large molecules made up of lots of phenols – they are useful antioxidants which trap oxygen radicals

Polyphenols are found in plants and are often brightly coloured. Tannins are polyphenols, and cause a characteristic “furry” taste in the mouth because they react with the protein molecules on the surface of our tongue. These molecules are powerful antioxidants. What does that mean, and why do plants make them? In the case of a grape, one of its main concerns is DNA damage by ultraviolet light. Although short wavelength UV light can directly damage DNA, it seems that less powerful, longer wavelength rays can generate very reactive oxygen radicals such as singlet oxygen and hydroxyl, which then combine with, and damage DNA. Polyphenols can rapidly “mop up” or detoxify these oxygen radicals and protect DNA.  If you live in the mountains of SW France, Sardinia, Crete or Sicily, the plants, and especially grapes, are subjected to large amounts of UV irradiation and produce lots of polyphenols. The people who live eat and drink lots of these polyphenols live to an unexpected old age. It might be a coincidence, but, for me, the inconvenience, expense and sheer tedium of drinking three glasses of red wine a day seems worth a try. But don’t overdo it and do remember Kevin (vodka and sweetbreads) below. The food link this week is a drink – Malbec.

Argentinian Malbec is full of tannins
Argentinian Malbec is full of tannins

This is a grape variety, which, according to Roger Corder, contains very high levels of procyanidins – tannins which he thinks helps protect us from heart disease and cancer, and makes us live longer.  Antioxidants prevent the oxidation of LDL cholesterol (see previous post on chest pain and horsemeat lasagne) and reduce DNA damage that can make normal cells malignant and age more quickly. It is grown in the mountains of SW France and is the main variety in Cahors wine – a particularly dark and astringent glassful. Argentinian Malbec is more available in the UK and is also grown high up in the mountains where it gets plenty of ultraviolet light.

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asbestos and black pudding

Some cancers are better than others. Mesothelioma is one of the worst. Alfred was admitted to our ward earlier this week. He is a 78 year old retired shipbuilder. He has mesothelioma in his lung. He spent most of his life in the Naval shipyards welding large plates of steel together to make warships. When he was young, a huge amount of asbestos was used in naval ships. It was packed in thick layers between the compartments of the vessel as it was being constructed. Alfred and his mates played snowballs with lumps of the stuff (of course, no masks were worn then).  Asbestos was used in naval construction because it is a refractory material. That means that it will not burn or melt even at high temperatures, so that it will prevent fire spreading from one part of the ship to another. It is also very cheap – a mineral that needs no further processing once it has been dug out of the ground.

Slide2
chrysotile asbestos
from Ra’ike – wikimedia commons

The reason Alfred came into hospital was because he had suddenly become more breathless and had bad chest pain when he breathed deeply. When we examined him it was clear that he had a large amount of fluid between his lung and chest cavity – a pleural effusion. We were also worried that he may have a pulmonary embolus. Patients with cancer commonly develop blood clots in their veins that travel to the lungs and block up the circulation causing shortness of breath, chest pain and even death if the clots are big enough.

His wife was with him. She knew he had cancer. She did not say it, but clearly she thought he was about to die.

We gave Alfred oxygen, an injection of low-molecular-weight heparin to prevent further blood clot formation and arranged a CT pulmonary angiogram.

Why is asbestos so dangerous?

The common form of asbestos is chrysotile. This is white asbestos. There is also brown, and the even more deadly blue asbestos. Chrysotile is a fairly simple chemical compound – magnesium silicate. Talcum powder is also magnesium silicate, but asbestos has a different crystal structure to talc. The crystals which asbestos is made of are very long, and very thin and break up into tiny, sharp needles. These needles get stuck into the lung and cannot be removed.

Ordinary dust commonly contains silicates. Sand is pure silicate. Silicon and oxygen are by far the two most common elements in the earths crust. Lots of stuff we use every day is made of silicates, including glass, ceramics (the cup you are drinking coffee out of right now), the bricks your house is made of, the cement mortar holding the bricks together, the surface of the paper you put in your printer, toothpaste etc. etc. The reason silicates are so useful is that the silicon-oxygen bond is very strong. This means when you put strong acids, alkalis or solvents in a glass vessel it does not dissolve. It also means that when it is in the wrong place in your body it can cause a problem because it cannot be broken down.

the granite worksurface, the ceramic tiles and grout, the pottery bowl, the glass and surface of the paper are made of silicates.
the granite worksurface, the ceramic tiles and grout, the pottery bowl, the glass and surface of the paper are made of silicates.

Ordinary dust, in reasonable amounts we can cope with. If it gets down into our lungs, it is trapped by the mucus layer on the surface of the tubes, or bronchi. This mucus is continually produced by goblet cells – called that because they have a goblet shape.

Mucus is a very wonderful substance. It is mainly water, but clearly not only water because it is very sticky. It is designed to be sticky to trap dust particles and bacteria. Bacteria don’t like to be trapped in mucus because they find it hard to move around – like us trying to swim in a swimming pool full of treacle.

treacle

Once the bacteria and dust particles are trapped, tiny, beating cilia on the surface of the bronchial epithelial cells move the mucus layer along. These cilia, which look like miniscule hairs, push the mucus, with its cargo of dust and germs, in one direction – upwards. Eventually, it reaches the larynx and then goes down the tunnel of death – the oesophagus – to end up in the acid of the stomach. No germs can survive this apart from helicobacter pylori – the subject of a future blog no doubt. The cilia are easily damaged. One reason smokers cough is because their damaged or absent respiratory cilia do not move mucus up the escalator, so it collects and needs to be coughed up.

Mucus is a wonderful substance made mainly of sugars. Sugars are essentially sticky substances. Lollipops are sticky, honey is very sticky. In earlier times wallpaper was stuck to walls with flour and water paste – wheat flour is composed mainly of starch –  a long polymer of the sugar, glucose.

wallpaper paste

Modern wallpaper paste is made of methylcellulose – a form of cellulose that dissolves in cold water to make something that looks quite like mucus. We use a lot of K-Y jelly in our work. It is also made from methylcellulose. I have read that many litres of K-Y jelly were used to simulate mucus in the Alien films.

The sugars in real mucus are quite special – they are in the form of long sugar chains known as mucopolysaccharides or glycosaminoglycans. I prefer the word mucopolysaccharide. It just means polysaccharide – a sugar chain – derived from mucus. They are special because unlike the common sugar glucose, many of the sugars in mucopolysaccharide chains have an amino group (NH2) and many have sulphate (SO4) groups attached. The sulphate groups make mucus even stickier.

The mucus produced by goblet cells is not just a solution of mucopolysaccharides. It is a complex structure. The goblet cell extrudes a long protein molecule called mucin. The sugar chains are attached to the mucin like bristles on a bottle brush.

Slide1
structure of mucus
the central red shaft is a protein to which many long sugary mucopolysaccharide chains are attached (blue)

So, on average, mucus has more than twice as much sugar as  protein in a large amount of water – rather like wallpaper paste.

Our bodies use mucopolysaccharides for a lot of things apart from making mucus. They are important in lubricating joints and are found in the jelly-like vitreous humor in our eyes. Some bacteria produce these sugars as a slime-coating or capsule which makes them more difficult for phagocytic cells to ingest. (See phlegm and horseradish previously).

Back to the asbestos particles. Being very thin and sharp, they manage to penetrate the mucus layer and get into the lung substance. They would not cause too much of a problem if it were not for the police in the form of macrophages. These officers of the law are very intolerant of foreign invaders and try to destroy them. (I’m not suggesting police are racist by the way). If the foreign invader is a bacterium then fair cop. If it is an organic substance like wood fibre, engulfing it and breaking it down is also a good idea. The problem with asbestos is that it is a silicate, and even though macrophages can make some pretty nasty chemicals, they cannot break down asbestos. It is like glass or ceramic. That does not stop the macrophage trying.

There is a great picture of a macrophage trying to eat an asbestos particle at the end of this imgur gallery:

http://imgur.com/gallery/nBJb6

When trying to dissolve foreign bodies, the nasty chemicals such as hypochlorite can damage DNA. This may be why asbestos exposure causes cancer, although the details are not clear at present.

There is one place in the body where foreign bodies do not cause inflammation – the anterior chamber of the eye. This is because the damage caused by cells such as macrophages would endanger our sight. The eye is known as an immunologically privileged site It means that we can put new plastic lenses in the eyes of patients with cataracts and graft a new cornea from donors without needing immunosuppressive therapy.

And now back to Alfred. He was found to have several large blood clots in his lungs. They had formed in his legs or large veins in the abdomen and travelled upwards and got stuck, reducing the flow of blood in his pulmonary arteries. We treated him with enoxaparin – a low molecular weight heparin. He got better quite quickly and went home with his wife a few days later. She looked much happier than when they arrived. We taught her how to inject her husband with heparin every day.

Heparin is a mucopolysaccharide, made from cow lungs or pig intestines. It is made from the slimy stuff on the surface of the tubes – the mucus. It is separated from the protein it is stuck to using enzymes and chemicals, and purified – the bristles are removed from the brush. We used to use this unfractionated heparin to prevent and treat blood clots.

heparin is a chain of sugars with amino groups and sulphate groups low molecular weight heparin has short chains of five sugars
heparin is a chain of sugars with amino groups and sulphate groups
low molecular weight heparin has short chains of five sugars

Now the long sugar chains are chopped up into five-sugar lengths – low molecular weight heparin. This is easier to give by an injection under the skin rather than into a vein. It is also more reliable in treating and preventing blood clots.

cartoon of fibrin breakdown - from Jfdwolff wikimedia commons
cartoon of fibrin synthesis and  breakdown – from Jfdwolff wikimedia commons

Heparin interferes with the horribly complicated cascade of events that leads to an insoluble protein – fibrin, being formed from the soluble clotting factors circulating in our bloodstream. The system is so complicated because it is vitally important. Stopping blood leaking out of holes in our blood vessels is pretty high up the list of things we have to get right if we are to survive as a species. The clotting cascade is designed to produce large amounts of fibrin clots very quickly when we need it – whether you are being savaged by a wild beast or crushed by a bus, clotting can save your life.  But blood clots in vessels without holes to repair can also be fatal. Alfred could well have died if he had not been treated with heparin.

Fibrin formation is responsible for forming clots in veins. It also strengthens the clots formed by platelets in arteries. The problem is that patients with cancer, or people who have been ill and immobile (or even after a long-haul airplane flight) can develop clots in their veins even when there is not a hole in them.

We suspected Alfred may have a blood clot problem because we found a high concentration of D-dimer in his blood. When a clot forms, say in the wall of an artery which has been damaged, it is remodelled by an enzyme called plasmin which dissolves fibrin. This shaves away the unwanted bits of clot to make them neat and fit for purpose. The fibrin turns into, among other things, D-dimer. Whenever there is a lot of fibrin clot around, the D-dimer level in the blood increases.

Now the food link. I’m particularly pleased with this one – black pudding.

black pudding
black pudding

I went to the butchers yesterday to buy some. I fried it with tomatoes, bacon and sausage for a late breakfast. Black pudding is made in the UK from pigs’ blood. It is cooked, which makes it clot, and mixed with oatmeal and herbs and stuffed into a pig’s intestine from which the inner surface or mucosa has been removed. Drug manufacturers use the mucosa to make heparin. So, black pudding is a large blood clot made in the very organ that gives us a drug for preventing blood clots!