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The masters of our minds: Meet the brain scientists battling to preserve our sanity

Wednesday November 24, 2010

MailOnline - The greatest threat to humanity is all in our minds - Parkinson's, multiple sclerosis and Alzheimer's affect millions, while one in six of us will die with dementia.

Andrew Preston put squeamishness aside to observe the brain scientists who are on one of civilisation's most ambitious quests: to prolong life itself.

All is quiet in Room E349 at London’s Hammersmith Hospital but for the gentle whirring of four six-foot-high freezers standing along a side wall. They are very cold – minus 80°C – and behind each is an emergency back-up of liquid CO2, in case the power fails.

Strip lights shine a chill, white light down onto the sparse contents of the sterile air-conditioned room. There are two steel sinks, a computer monitor, a microscope and four shelves upon which identical white plastic containers are lined up, their lids firmly on, each one numbered in black marker pen.

A large steel bench straddles the centre, and is perforated for drainage and cleaned by a steady down-draught, which sucks any vapours or smells down and away. On it sit two cutting blocks, each with a triangular guide frame, a sharp knife, a scalpel, blue tweezers and several turquoise plastic sample cases.

The silence is broken at 10am when neuropathologist Dr Federico Roncaroli and neuroscientist Dr Steve Gentleman use their swipe passes to enter through the blue security doors. They put on disposable plastic overalls and purple nitrile rubber gloves, reach into a container, numbered 4273 and 4563, take out the contents, place them on the cutting block and pick up a scalpel.

They are here to help advance a vital cause. To identify, delay, and perhaps eventually prevent the onset of devastating illnesses that will affect increasing numbers of us as the population ages: principally Alzheimer’s, dementia and Parkinson’s disease.

They will also observe the damage inflicted on our brains by our ‘lifestyle choices’: smoking and drinking. To do this they must dismiss any thoughts of squeamishness they might have at the sight of the organ before them and at the thought of what they must now do to it.

The human brain is heavier than you might expect. It weighs in at 3lb – that’s two per cent of the body weight of an average person – and consists of water, fat and protein. It is a tightly packed housing of 100 billion neurons, or nerve cells, which signal to each other by generating and passing on electrical signals.

These shuttling signals coordinate every action of the body and produce every thought, memory and feeling. But what we know about how the neurons do this is dwarfed by what we do not know.

When we are born, our brains are a quarter of their eventual adult size; by the age of one that rises to 75 per cent and it is almost full size by the age of eight. But from the age of 20, that goes into reverse: it decreases by about 1g per year.

Advanced imaging techniques (like CT and MRI scans) have built up a picture of the anatomical structures inside the living, working brain. Others (like PET and fMRI scans) have gone further, revealing how the brain functions by showing which parts are firing. This is done by measuring alterations in blood flow and glucose absorption.

But like a man reporting from the Moon’s surface rather than inspecting it remotely with a telescope, the biggest understanding comes from examining the real thing.

Once out of its container, the brain’s coiled mass of beige, gelatinous wrinkles looks strangely beautiful. It is rubbery and firm to the touch. It’s unnerving when you realise that the person this came from was alive just a few weeks earlier.

Dr Gentleman, however, is entirely pragmatic.

‘I absolutely don’t feel squeamish,’ he says. ‘It’s out of context, isn’t it? I have huge problems in equating this to a person. Instead I see it as a route to finding a cure.’

The brain tissue bank at Hammersmith run by Imperial College has 20 freezers and currently holds 400 brains from people who had Parkinson’s, 503 multiple sclerosis brains and 90 ‘control’ brains. The control brains don’t have, or at least don’t appear to have, any evidence of disease and so can provide scientists with a basis for comparison.

Major progress in this science has only been made relatively recently. The Egyptians would discard the brain before mummifying a body, while to Aristotle it was a mere secondary organ. To him it helped cool the heart, which he regarded as the most important organ. It was only life-changing accidents like that of American railway foreman Phineas P Gage that helped give a picture of how the brain works.

Gage survived an explosion in 1848 in which an iron rod was driven into his head. He went from being a quiet, good-natured and reliable worker to surly, ‘grossly profane’ and unable to hold down a job. From this, doctors and scientists came to realise that specific brain areas control personality and behaviour, in this case the brain’s frontal lobe.

The case of Henry G Molaison helped further. In 1953 surgeons removed an extensive area of the hippocampus, towards the back of his brain, in order to halt severe epilepsy. From then on everyday events would stay in his mind just fleetingly, and whenever he met people he already knew he didn’t recognise them. This helped lead to the realisation that the hippocampus is vital for memory storage, as well as spatial navigation. It is an area attacked by Alzheimer’s disease.

Dr Alois Alzheimer discovered the disease in 1906 after examining the brain of a woman who died in her fifties and had suffered short-term memory loss. Now some 820,000 people suffer with dementia in the UK (two-thirds of them with Alzheimer’s), which costs the country an estimated £23 billion in NHS and social care, and the work of unpaid carers. The number of people affected is predicted to double in the next 30 years, largely because we are living longer.

‘Research using brain tissue remains vital to help us halt the progress of diseases like Alzheimer’s,’ says Dr Safa Al-Sarraj of King’s College Hospital, London, which coordinates the Brains for Dementia research network of five tissue banks. It’s an uphill struggle though: for every £1 spent on cancer research, only 8p is spent on dementia.

While a cure for the disease remains a distant prospect, there is still hope that research to combat Alzheimer’s and other neurological disorders like Parkinson’s disease and multiple sclerosis might help us live longer.

‘Research is like doing a 5,000-piece jigsaw without the picture,’ says Dr David Dexter, director of the MS Society/Parkinson’s UK tissue bank run by Imperial College.

‘You start with the boring bits, putting down the straight edges, which is what scientists have been doing for the past few years. The jigsaw for Parkinson’s is really coming together now, and very interesting and novel therapies are starting to come out that wouldn’t be happening if we didn’t have the brains on which to do research.’

‘My bleeper went off at 5am on Saturday,’ says Dr Dexter. ‘It was news from his stepson that a registered donor had died in East Anglia. A GP signed the man’s death certificate, which was fortunate because normally GPs on call at the weekend won’t sign if it is not one of their patients. We then approached the local hospital to see if they had on-call mortuary staff. The man had died not far away from Ipswich and the facilities manager there said he was willing to come in – we pay mortuary staff £100 to take the tissue out.’

‘Fresh’ brains, and if possible the spinal cord, are especially prized, because if frozen immediately scientists can preserve all of their structures, enzymes and genetic information. But the race to get a brain to the tissue bank within 24 hours is fraught and relies on a lot of things falling into place. First as a donor you need to be registered; then a GP and local hospital and funeral staff need to be available, so Sundays can be a problem.

‘We liaised with the family to move the body from home to Ipswich,’ continues Dr Dexter. ‘At the same time one of our technicians jumped on a train from London. His job was to bring the tissue back to the brain bank here in a leak-proof metal container surrounded by ice blocks in what looks like a picnic bag.

'They travel with documentation explaining what they are carrying, but we have had problems in the past bringing tissue by plane back from Northern Ireland. The containers had to be opened up and inspected because, on X-rays, brain tissue shows up the same as Semtex plastic explosive.’
Normal organ donor cards do not cover brains. Celebrity donors have helped raise awareness – those to have signed up to donate include Jeremy Paxman and Jane Asher, whose brother-in-law has Parkinson’s – but brain banks do still need new pledges.

‘Control’ brains are in particularly short supply, and for research into Parkinson’s, for example, Imperial College needs donations from different ethnic groups – as well as people with younger-onset disease, diagnosed under the age of 45, who are prepared to have their brains monitored as the disease progresses.

The purpose of the brain bank is twofold: to provide tissue for research projects and for the detective work of its neuropathologists, who can offer a definitive post-mortem diagnosis. Approximately 17 per cent of people diagnosed with Parkinson’s are later found not to have actually had the disease once brain tissue is examined.

Although a definitive diagnosis can only be made once cells have been looked at under a microscope, even during the initial cutting some clear signs of disease can be spotted.

‘In the case of Alzheimer’s you’re looking for shrinkage mainly and the troughs on the surface would become wide and the crests narrower,’ says Dr Gentleman from Imperial College. In some cases the decay can be so extreme that the relatively smooth surface can be transformed to look like a moist, overgrown walnut.

‘With Parkinson’s disease, a major area we look at is the thumbnail-sized substantia nigra, which, as the name suggests, should show black pigmentation.’

If the dark pigmentation has turned pale this means there has been a degeneration of cells that help control muscles and movement, explaining the tremors and motor problems associated with the disease. Evidence of multiple sclerosis can appear as lesions or scars showing damage to the myelin, the fatty insulation around the axons in the nerve cells that helps messages travel quickly and efficiently.

Once at the lab the ‘fresh’ brain is cut in half, sliced into 1cm thick slices, and samples taken which are snap-frozen for future research using supercooled liquid isopentane. This freezes the tissue very rapidly ready for storage so that whenever it is used in the future all the cells are perfectly preserved, with DNA and RNA information (the two of which make up the genetic material of cells) intact.

The other half is put in formalin, to preserve it. A few weeks later this tissue is cut into 1cm-thick slices and 2cm-square blocks and put into small plastic cases. These blocks are then ‘processed’ with a variety of fixative liquids before being embedded in paraffin wax.

Once set, thin sections, just six microns across (that’s six-millionths of a metre, even thinner than a red blood cell, which is eight microns wide) are taken from the block using a microtome (known among hard-headed staff as ‘the bacon slicer’). The slices are put on a slide and are then ready for microscopic analysis, including staining with coloured dyes or antibodies, which can show up evidence of disease and help with making a diagnosis.

Research has proved that size doesn’t matter when it comes to brains; the way a brain is wired inside is far more important. Dr Dexter remembers technicians having a running game trying to guess the sex of the brain just by looking.

'Female brains generally, but not always, are slightly smaller,’ he says, ‘but that is in proportion to body size. They have more or less the same number of neurons but these are packed into a smaller space. The brain is quite a sexually dimorphic structure though – women are more susceptible to stroke, whereas men are more susceptible to Parkinson’s disease.’

And what about unusual brains? Would he, for example, be able to recognise the brain of a genius?

‘I don’t think you would really see any differences – if you put Einstein’s brain in front of us, we wouldn’t know it was his,’ says Dr Dexter.

The difference between a computer now and a computer in the early Nineties is the connections, and the brains of humans are similar,’ agrees Dr Al-Sarraj.

‘We have the same number of neurons – our brains had the same number of neurons when the Pharoahs were around – but the connections in our brains and the synapses (the gaps between neurons bridged by chemicals called neurotransmitters) now work much better. We can correlate things better and understand things better. That’s why Einstein’s brain is different… he could see and understand things I cannot understand – the connections in his brain were different to mine.’

Samples taken from brains are used to investigate correlations between clinical symptoms and post-mortem findings, possible genetic causes and predispositions to disease, and to evaluate new drugs.

‘Cure is quite an emotive term,’ says Dr Dexter, of research into Parkinson’s. ‘Basically I think the first goal is to keep people at the level at which they are when they are diagnosed. Once we can find out who is going to develop the disease then if you apply a treatment early enough you may be able to prevent it. Finding the mechanisms has to be done with tissue itself, and animals don’t suffer from Parkinson’s, so that means human tissue.

‘Ten years ago we didn’t know the mechanism behind the dying of cells, but now we have clues. At the moment we can treat Parkinson’s symptoms, but clinical trials start next year on treatments to stop cells dying and slow the disease down.’

‘Ideally we need to diagnose the disease before it becomes clinically obvious, by which time a lot of the damage has already happened,’ adds Dr Gentleman. ‘Our realistic aim is to stop whatever the underlying process is. I think it’s way into the future that you’ll actually be able to reverse any changes.’

Progress, however slow, also continues to be made into tackling Alzheimer’s – the development of current drug treatments for dementia would not have been possible without studying brain tissue.

‘With a donation of a heart you see an immediate benefit, but with the brain it takes time,’ says Dr Al-Sarraj.

‘There are research projects which are about to break through to halt the progress of Alzheimer’s. Then you would at least be able to plan your life while you still have some mental capacity. If we can stop its progress then it could become like diabetes so that people can live with it.

I will be 60 in a few years’ time and if I get dementia I will be out, but maybe in the next generation people will get dementia but be able to deal with it and keep working for a further 15 or 20 years. ’ Dr Al-Sarraj will donate his brain for research, as will Dr Dexter.

‘Years ago there was a lot of bad publicity about organs being taken without consent,’ says Dr Dexter, ‘but since the Human Tissue Act in 2004 everything is now much more regulated.

'If you tell the public the truth, take the mystery out of it and explain exactly why it’s important to donate, then I’m sure more people would sign up. I think once I’ve finished working here I would donate. But if I died while I was still here then I would be asking my colleagues to dissect me and I don’t think that’s fair.’

In the meantime, do they have any tips on how to look after our brains?

Dr Dexter has one strong piece of advice, thanks to a sideline of research he is doing into ‘Italian binge-drinking rats’: watching the damaging effects this has on the hippocampus of their brains, and hence on long-term memory. From his research so far he can safely say ‘binge-drinking appears to have a hugely harmful effect on the brain’.

As for looking after his own, he admits, ‘I take flavonoid pills which I get from America, including tangeretin, which is present in the peel of tangerines, and which protects neurons and can slow down the ageing process, and also selenium which boosts the immune and anti-oxidant system.’
Both Dr Dexter and Dr Al-Sarraj claim exercise and keeping an active mind are important.

‘If once you stop working you don’t do anything you could succumb to neuro-generation quickly,’ claims Dr Al-Sarraj.

‘Keep yourself busy and mentally agile by exercising your brain. You need to be challenged as a person. As for supplements like antioxidants and vitamins we need to know more. I don’ t take any but if you go to a conference of neuroscientists, people won’t actually openly say they take anything to keep their brain in good order. But ask anyone there who doesn’t take them to put up their hand, and no hands will go up.’

As he respectfully places the remaining brain tissue back in its container in Room E349, the dissection complete, Dr Gentleman points out yellowy deposits on a blood vessel going into the base of the brain, which could be signs of a high fat diet or smoking. His advice is moderation.

‘Don’t smoke, obviously, plus think about diet and exercise. In the Alzheimer’s field it’s becoming clearer that it’s those general lifestyle factors that affect your subsequent risk of deterioration. It’s not going to protect you completely but you do lower the risk.’