The missing link in heart disease

It is 1969 and a young Harvard research graduate, Kilmer McCully, is working in his laboratory in Boston with feverish energy. He has stumbled upon a vital clue to the cause of heart disease and he thinks his discovery could change the course of modern medicine. "I was so excited, I had difficulty sleeping for over two weeks," he recalls.

He had had a hunch while studying a rare and fatal genetic disease, homocystinuria, in children. He rushed back to his lab to examine slides from the organs of a two-month-old baby boy who had died shortly before of the condition. Now, after some inspired detective work, he is sure his hunch is right.

What McCully saw in front of him all those years ago was that the arteries of this tiny child were severely damaged. They looked like those of old patients who have died of heart attacks or strokes. Yet the baby was obviously too young to have lived in any of the ways that were supposed to lead to heart disease. He was too immature to have consumed too much fat, too small to have failed to exercise, and too innocent to have smoked. There was no cholesterol deposited in his artery walls. Something else had to be responsible for the clogging up of his blood vessels that had led to his death.

McCully remembered two previous cases of children who had died of homocystinuria. He re-examined the slides from their autopsies. There was his clue again - they too had damaged arteries. The culprit in all three cases was homocysteine.

Homocysteine is an amino acid [see box] and children with homocystinuria lack the enzymes to process it properly, so it builds up to dangerous levels in their blood.

"Chance favours only the prepared mind," according to Louis Pasteur, and McCully had by chance trained not only in medicine and pathology but also in biochemistry and molecular genetics with the discoverer of DNA structure, James Watson. He was able to make those great leaps and connections that characterise scientific breakthroughs. He was also peculiarly qualified to realise the enormous implications of what he was seeing.

Heart disease was sweeping the western world like an epidemic at the time, claiming hundreds of thousands of lives. Today it is still Britain's biggest killer, leading to premature death in more than 175,000 people a year - that's more than all cancers put together.

The pharmaceutical industry has made a fortune selling drugs to prevent it. Vast sums of money and distinguished acedemic careers have been devoted to trying to find out what causes it. Supermarket shelves are filled with high-priced, low-fat products designed to help you avoid it. Yet there are lots of unanswered questions about the prevailing view of heart disease, and in particular the idea that fat and cholesterol are to blame.

McCully realised that if he was right, and homocysteine was the culprit, the experts might have been barking up the wrong tree. What's more, since homocysteine levels can be controlled by taking vitamins B6, B12 and folic acid, cheap supplements might be more effective than expensive drugs or guilt-inducing fat subsitutes.

McCully sent off his observations to a respected scientific journal for publication. He felt that his homocysteine theory made sense of some of the previously inexplicable statis tics. More than half of those who have heart attacks have no recognisable risk factors, for example. He didn't yet fully understand the mechanisms but he was looking forward to open debate with others studying heart disease. "I hoped it was significant. I had a big laboratory at Harvard. I assumed it would all be welcomed," he says.

Nothing could have prepared him for the violence of the reaction to his findings. Far from being feted, he was frozen out and ostracised, his career brought abruptly to an end.

Today, McCully's homocysteine hypothesis is the theory of the moment. Nine major randomised controlled trials on preventing heart disease by lowering homocysteine with vitamins are now being conducted around the world. Six months ago, in the Lancet, leading stroke and heart disease expert Graeme Hankey concluded that homocysteine was firmly back as a prime suspect in heart disease. "The association is independent of other factors, it is strong and it is biologically plausible," he says. Last year McCully was awarded the prestigious Linus Pauling award for his contribution to medicine.

His revolutionary idea has been vindicated but it has taken a lifetime - three decades, during which more than four million people have died of heart disease in this country alone - for the medical establishment to recognise the significance of his discovery.

Why did it take so long? McCully himself has had plenty of leisure to puzzle over it. "Why should a quarter of a century of medical science elapse and a whole new generation of scientists mature before the significance of an important new theory of dis ease is recognised and properly explored?" he asks. The answers give a telling glimpse into the savage politics of medical research and drug company profits.

Among McCully's peers at Harvard in the early 70s were leading experts in the cholesterol field. As early as the 16th century, anatomists in Renaissance Italy had made a connection between wealth, social standing and abnormalities of the arteries. Earlier still, Leonardo da Vinci had noticed atherosclerosis in his dissections of the human body. By the 1970s, the idea that heart disease was an illness of the affluent was firmly established. The view that eating too much fat was the cause had become almost unchallengeable. But McCully didn't want to demonise fat; he thought the problem was more to do with protein poisoning. And ironically deprivation, in the form of overindustrialised food production rather than affluence, was at the bottom of it.

Given that some of his colleagues had invested a lifetime's work in pursuing their particular lines, their hostility was perhaps predictable. "People get very emotional about their theories," McCully says - they don't like their previous research criticised. But he still finds himself stunned by their behaviour. "They told me I hadn't proven my theory. They took away my lab and put me in the basement. They threatened me and said if I couldn't renew my funding I was out."

McCully tried to find other posts where he could continue his research and support his family. Each time he got an interview but failed to get a job. A former colleague attacked his ideas as "arrant nonsense". The public affairs director of the Massachusetts general hospital "told me to shut up".

McCully ended up in a relatively obscure post at the Veterans' Hospital in Rhode Island. It became almost impossible to get funding for his research, and although he continued work on his exciting breakthrough, his glittering career was over. He was ignored for the next 30 years.

McCully's timing had proved disastrous. "The mid-70s was exactly the time of the big lifestyle trials that were meant to prove the cholesterol/excess fat theories. These cost over £100m. There was a need to squeeze out dissidents in order to assert the orthodox line," says Dr James Le Fanu, whose book, The Rise and Fall of Modern Medicine, examines in devastating detail how politics got in the way of open debate.

But there was more at stake than the inflated egos of a few academics. In the early- to mid-70s the drugs companies were producing new cholesterol-lowering drugs. They had invested heavily in them and needed to market them aggressively to doc tors. Research undermining the cholesterol theory would also undercut profits. They were not likely to put up money to investigate a discovery that might deprive them of their returns.

Those returns have been enormous: by the mid-90s, hundreds of thousands around the world were taking cholesterol-lowering drugs and more than £3bn was being spent on them. The trouble was, they made people feel rather sick, and "they didn't actually reduce total mortality," as Andrew Herxheimer, a pharmacologist and emeritus fellow at the NHS research programme, says. By 1992 there were calls for a moratorium on their use.

Undaunted, the pharmaceutical industry was working on a new kind of cholesterol-lowering drug, a group called the statins. "They do lower mortality, but few drugs have only one action," says Herxheimer. Some experts think statins may work partly because they change blood clotting mechanisms. Aspirin is also an anti-clotting agent and has been a phenomenal success in reducing strokes, heart disease and dementia, but "it's very cheap and it doesn't make money, so most drugs firms are not interested," says Professor Peter Elwood, of the University of Wales College of Medicine, who has done pioneering work on it.

The cost to the NHS of cholesterol-lowering drugs, 90% of which are now statins, has soared from £34m in 1992 to £190m last year. "The drugs companies always want them more heavily prescribed," says Herxheimer. "If the homocysteine story is true, there is nothing much in it for them."

McCully's story has a familiar ring for Charles Medawar, who set up Social Audit to campaign for consumers on medicinal policy. He points out that when Barry Marshall, a doctor in Australia, discovered that ulcers could be cured by simple antibiotics, making lucrative antacid drugs redundant, he was similarly mocked and disregarded.

The problem, argues Medawar, is that the drugs companies overwhelmingly control research. "There are areas where they now support whole university departments of pharmacology. There is a huge intolerance of deviation from commercial objectives. The penalties of breaking ranks are very high."

Herxheimer agrees: "The drugs industry shouldn't have such control over research agendas. It's very unhealthy."

In fact, deaths from heart disease have declined rapidly since the 60s in the USA and since the late 70s in the UK. Cholesterol levels haven't changed that much, and nor has our diet, except perhaps in one signficant way. In the mid-60s, food manufacturers started fortifying food and in particular cereals with B vitamins. Fortification came about a decade later here, and folic acid is now being added too - the very vitamins, as McCully pointed out, that control homocysteine.

McCully is remarkably philosophical about what happened to him, but admits: "I've had a hard time. It's been 30 years." Meanwhile about 300,000 people in the UK still have heart attacks each year, and about half of those are fatal. "If I had been allowed to stay at Harvard, it would all have come out earlier. I had hoped it would make a difference."

Protein poisoning The homocysteine hypothesis

Homocysteine (pronounced homo-sis-teen) is an amino acid which our bodies uses to build tissues. We derive it from another amino acid, methionine, which is found in animal protein - meat, milk and eggs. But too much homocysteine in the blood increases your risk of heart disease.

In test-tube studies, homocysteine has been shown to injure blood vessel linings, to hasten the build-up of scar tissue, and to encourage blood clots. You can control levels of homocysteine by making sure you have enough B vitamins to break down any excess, in particular B6, B12 and folic acid. If you are deficient in these vitamins, homocysteine seems to attack the walls of the arteries. We get these B vitamins from fresh green vegeta bles, fruit and whole foods but they are easily destroyed by processing. Homocysteine could help explain the other risk factors for heart disease. Smoking and inactivity lead to raised homocysteine levels. Men are at greater risk of heart disease than women and during their reproductive years, women's homocysteine levels are about 20% lower than men's.

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