Science: Radical treatments

Brain cells retrieved from dead bodies have been revived with huge doses of oxygen, reports Hilary Bower. But essential as it is to life, it may also be the stuff that kills us
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EARLIER THIS YEAR, in a pathology laboratory in Amsterdam, three Dutch neuroscientists managed to do what no one had thought possible. They brought brain cells from 30 dead people back to life.

In a ghoulish but fascinating experiment, the scientists took specimens of brain tissue during post-mortems up to eight hours after death. Into it they delicately injected tracer chemicals that can only move along the spidery fibres that connect one neuron to another if a cell is alive and firing its electrical messages. They then incubated the apparently inert cells in a warm bath suffused with a gas made up of 95 per cent oxygen and 5 per cent carbon dioxide - almost five times the oxygen content found in normal air.

After 18 hours, Jaipei Dai, Dick Swaab and Ruud Buijs removed the brain cells from the bath and tracked the path of the tracer chemicals. What they found was that the "dead" neurons had fired the tracers across the tissue, just as they would had they been in a warm, live brain.

Writing up their study in the medical journal the Lancet, the scientists say these startling results could have huge implications for treating what's long been thought of as irreparable brain damage, whether through stroke, cardiac arrest or accident. And well they might, says Professor Philip James, another exponent of the use of high- dose oxygen to treat cell death.

An industrial physician at Dundee's Ninewell's Hospital, Professor James is also an international expert in the use of "hyperbaric" (pressurised) air. Most often used to help patients accidentally exposed to low-oxygen environments, the increase in pressure means that oxygen is taken into the bloodstream in far greater quantities. Accepted wisdom says that if you have a stroke, the area of the brain which has been deprived of blood and therefore oxygen (usually by a clot), will die in four minutes. Yet, says Professor James, these Dutch scientists managed to persuade brain cells to fire again eight hours after their bodies were certified dead.

"It's remarkable. What they have shown is that brain cells don't die completely for some considerable time, they're just 'sleeping'."

The key, says Professor James, is the proper use of oxygen - the primary substance the brain is deprived of in a stroke. "Most doctors say if you have a stroke, that area of the brain is dead and that's the end of it, we can't do anything about it. Most neurologists also accept that there is a much larger area known as the ischaemic [blood-starved] penumbra that isn't dead, but is physiologically traumatised, but they don't know how to treat it and so eventually it does die. Yet here we have tissue functioning up to eight hours after death, given intense doses of oxygen."

In the US, researchers who put acute stroke victims in a hyperbaric chamber to breathe oxygen at 1.5 times normal atmospheric pressure reported this summer that the number of patients who could be discharged from hospital within 24 hours dramatically increased, while in Britain, members of the Hyperbaric Oxygen Trust say by the use of oxygen under pressure, they have revived activity in the brains of people injured by accidents or conditions such as cerebral palsy after years of disability.

The explanation, they claim, is that when something - whether it's a blocked artery, a wound or inflammation - reduces the amount of blood (and therefore oxygen) reaching an area of the brain to a trickle, the affected cells are put into a sort of suspended animation because they only get enough oxygen to survive, not to function. Breathing pressurised oxygen, however - which Professor James stresses is just normal everyday O2 - raises the concentration of oxygen in the blood, thereby increasing the number of oxygen molecules getting through without having to increase the flow of blood into the area. The oxygen jolt wakens the cells from their sleeping state and gets them working again, allowing repair mechanisms to go into action.

If these controversial therapies prove correct, they provide just one more example of something we already know - that oxygen is our life-giver. It is the body's essential power source, the firelighter without which we'd be unable to turn food into the energy that drives the muscles and nervous system that maintain our life.

Yet paradoxically, even as some doctors turn to oxygen to heal - and the American trend is increasing for going to "Oxybars" for a maskfull of pure O2 to enhance brain power and concentration (see box, left) - it seems we can't live with this molecule either. More and more evidence is accumulating that while the beneficial face of this vital gas energises our tissues, its alter ego - the free radical - is sneaking around behind the bike sheds, beating up the same cells and shortening all our lives.

Free radicals are the chemical molecules given off by our cells as oxygen is metabolised for energy. Their identifying feature - and fatal flaw, for our health at least - is that they have one unpaired electron. As a result, they are always "on the pull" for a partner. Despite having lives just nanoseconds long, they can wreak havoc on almost anything in the cell simply because they engage in chemical reactions with whatever they bump into. Since oxygen is constantly metabolised to keep us fuelled, they are created all the time in all our bodies, and there is plenty of scope for these hyperactive singles to do damage.

Their cruising lifestyle now appears to be at the heart of this century's most deadly diseases, says Professor Anthony Diplock, president of the International Antioxidant Research Centre in London and a long-time investigator of free radical havoc.

Free radicals can not only modify cell enzymes and proteins, tripping a whole series of chemical dominos that shouldn't take place, their ceaseless search for a partner is also responsible for about 10,000 DNA modifications every day. This is largely because one DNA base - guanine - is particularly susceptible to their charms and gives up its electrons at a glance. The changes this provokes can block cell replication, cause mistakes or changes in the copying, or prompt cells to speed up division - all of which set the scene for the kind of cell abnormalities known to be at the root of cancers.

"We're fairly sure that free radicals are involved in causing mutations," says Professor Diplock, "but what we don't know yet is exactly what the link is between this damage and actual carcinogenesis."

However, when it comes to heart disease and other conditions such as stroke and dementia, caused by faulty blood circulation, the damning evidence is much clearer. Free radicals are now known to trigger one of the first steps - the oxidation of low-density lipoprotein ("bad cholesterol") - in the formation of the fatty sludge known as atheroma that builds up on artery walls and narrows vessels.

Under normal circumstances, says Professor Diplock, "antioxidants" - chemicals which are created both from food and naturally in our cells - keep free radicals in check. These chemicals simply give free radicals one of their electrons before they get one from a more fragile source, in other words antioxidants quench the threat free radicals represent by giving them the electron they're after. But the combination of fast- food diets, lacking in antioxidant-bearing fruit and vegetables, plus environmental factors such as smoking, pollution and stress (all of which increase free radical production in our bodies) means the balancing act is out of sync.

A suggested answer to the free radical problem has been to take extra antioxidants such as vitamins A, C and E, and selenium and bioflavenoids in pill form. But Professor Diplock cautions that despite the enthusiasm of health food shops and vitamin manufacturers, the jury is still out on whether swallowing such supplements provides armour against cancer in humans. "Over 200 epidemiological studies show that a high fruit and vegetable intake gives a lower rate of cancer - but this could be because there are lots of goodies in fruit and veg, antioxidants may not be the causative agent. There is only a little evidence that actual intake of vitamins C and E lowers the risk of specific cancers in humans."

There is better evidence, however, for an antioxidant role in changing the course of heart disease. Studies in which people have been given high doses of vitamin E - 200mg-plus a day, almost impossible to get in food - have shown a lowered incidence of angina and a striking reduction in the rate of heart disease, says Professor Diplock. "It's something like a 45 per cent reduction - which is powerful magic."

Vitamin E appears to have a particular link to circulatory disease, although why it works better than other antioxidants is as yet unknown. But recent research also suggests the vitamin may have a big impact on neurodegenerative diseases such as Parkinson's and Alzheimer's. "It probably can't reverse these conditions, because there's little to suggest that it can diminish existing atheroma, but it seems to slow it down," notes Professor Diplock.

But taming the role of the free radical in disease may not be enough. Research increasingly suggests that the oxygen that keeps us alive is one of the factors that helps bring about our deaths, according to Tom Kirkwood, Professor of Biological Gerontology at the University of Manchester.

"At first sight it is paradoxical that something we depend on for life can be so harmful to us. On the other hand, petrol gets us from A to B but is also dangerous stuff if it's splashed outside the tank. Oxygen is known to be a dangerous substance: the same power that is harnessed within the pathways of the cells to our benefit can also do a great deal of damage.

"There is strong evidence that free radical damage is a key contributor to the ageing process, gradually overloading our natural repair mechanisms and allowing mistakes to accumulate in the way our bodies function," says Professor Kirkwood.

There have also been recent studies which show that fruitflies whose natural antioxidant production is boosted by genetic manipulation live significantly longer. But for humans, as yet, Professor Kirkwood believes, real evidence that boosting antioxidants will help us fight ageing is still thin on the ground.

And until such evidence is forthcoming, oxygen will remain the double- edged sword on which we both live and die. !


OXYGEN, according to some, is the molecule that reaches the parts others can't. "Take one breath of purity to clear your body and mind" - that's the promise written on the sides of the oxygen cylinders now available in the mini-bars of London's exclusive Hempel and Blake's hotels. The gas is supposed to calm nerves, combat city pollution, reduce jet lag and increase alertness.

You wouldn't have thought they'd need it with all those big skies and mountain air, but it was Canadians who introduced the concept of "recreational oxygen". The O2 Bar opened in Toronto last year, selling bursts of "natural" and fruit-flavoured oxygen (administered through a tube in the nose) in place of alcohol. Oxybars in New York and the Far East followed. Here, small cylinders containing about 10 minutes' worth of oxygen are available in the pharmacies of Harrods and Selfridges at around pounds 10 a throw.

Manufacturers say the gas can combat fatigue, lapses of concentration, anxiety and breathing difficulties. Fans say it makes them feel calmer and more alert, others say it does nothing at all. Which is not surprising, according to Dr David Bradley of the Royal Free Hospital medical school in London. "Taking a few puffs won't do you any harm because it doesn't do anything. The air we breathe is 21 per cent oxygen, which is more than enough for our needs. Blood is basically saturated with as much oxygen as it can carry at normal atmospheric pressure and it won't carry any more unless you increase that pressure."

And as for boosting alertness and all the other claims, he believes it's "all bunkum". However, researchers from the University of Northumbria's department of psychology beg to differ. In trials, David Scholey found that giving subjects doing learning tasks a short burst (30 to 60 seconds) of pure oxygen made a significant difference to what they retained. "The brain is tremendously active - it uses 20 to 30 per cent of the body's energy and that's when you're just sitting around - you don't have to be doing calculus. The brain uses two fuels, glucose and oxygen, but it can't store either, so our hypothesis is that the burst of oxygen may give the brain extra fuel at a time when it needs it," explains Scholey, who admits that there is still plenty of research to be done.