The Truth About Genetically Engineered Insulin by Jo-Ann Goodwin

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Daily Mail
August 29, 2002
http://www.gmwatch.org/archive2.asp?arcid=5225

Tainted crops in our fields. Superweeds that can't be killed.
Fears over mutant cattle, fish and pigs. Recent weeks have brought
alarming revelations over GM technology. But does this special Mail dossier
reveal the biggest scandal of all?
By Jo-Ann Goodwin

Jonathon was 19 years old when he died. Tall and strongly built, he was a keen all-round sportsman with a particular passion for football. He had chosen to study law after leaving school, and quickly settled in at Southampton University. On the last night of his life, Jonathon shared a curry with his flatmate, Ben. Exams were looming, and the two students spent a while revising before going to bed. Next morning Jonathon failed to turn up for football practice. His body was discovered later that day. He had died in bed some time in the early hours of April 23, 1995.

To this day, his mother Cheryl is haunted by memories of the police arriving at the door of her Midlands home to break the news. But what haunts her even more is the terrible possibility that Jonathon was killed by the very medication he was taking to keep himself alive.

He had been diagnosed as diabetic just before his 17th birthday. And like almost all sufferers in recent years, he had been prescribed genetically engineered 'human' insulin, commonly - and rather misleadingly - referred to as 'human' insulin.

Diabetics need insulin to prevent their blood sugar levels spiralling out of control. But in Jonathon's case, something went catastrophically wrong. The cause of his death was officially recorded as hypoglycaemia -meaning that the level of glucose in his blood had plunged so low that his body effectively ran out of fuel. 'Hypos' of varying severity are a constant hazard for diabetics, but in the months before his death Jonathon had suffered them with increasing frequency. They would strike without warning, leaving him disoriented and on the brink of collapse.

His mother now believes that there was a simple and deeply disturbing explanation: Jonathan's body was unable to cope with genetically engineered insulin. 'He was put straight on it as soon as he was diagnosed, , she says. 'No one told us there was any alternative. It was only afterwards - when it was too late - that I found out that things could be different.'

Indeed, as Jonathon's mother has discovered, his death is part of a far wider story.

Since its introduction 20 years ago this summer, genetically engineered insulin has been linked not only to an increasing number of unexplained deaths but to a range of side-effects that some patients say have destroyed their lives. These range from unexpected hypos to massive weight gain, violent mood swings, memory loss, joint pains, mental confusion and crippling exhaustion.

Complaints have been voiced by thousands of diabetics around the world. But they have failed to stop human insulin almost completely replacing insulin derived from pigs and cattle - although the animal insulin doesn't seem to have the same effects. In a striking echo of the MMR controversy, those who dare to question official policy have been vilified as alarmists. Tony Blair, for one, has hailed human insulin as a shining example of the benefits of GM technology.

Now, according to campaigners against human insulin, the need to challenge such complacency has never been greater. They fear that recent developments in the pharmaceutical industry could soon choke off all remaining supplies of alternative medication. They speak of feeling 'the noose tightening around our necks', and warn that more tragedies like Jonathon's are inevitable unless urgent action is taken. Now their campaign has received a major boost with the publication of a damning report on research into the new insulin. It challenges the reliability of trials that supposedly gave the product a clean bill of health. Concerns over GM technology tend to concentrate on the crops in our fields and food on our plates. But insulin is a substance that thousands of diabetics inject directly into their bodies every day. For the drug companies involved, millions of pounds in profits are at stake. And as the unsettling saga shows, profits can sometimes seem to be more important that the interests of patients.

At the beginning of the 1980s, two corporate giants were engaged in a breakneck race. Eli Lilly and Novo - later to become Novo Nordisk - were vying for control of the lucrative worldwide insulin market. Previously, all diabetics had relied on animal insulin extracted from the pancreases of pigs and cattle. But the bright new dawn of biotechnology had arrived, and Eli Lilly had succeeded in cloning a synthetic form of the insulin molecules found in the human body. It was an astonishing breakthrough - but Novo already held 40 per cent of the UK insulin market and had no intention of losing it to Eli Lilly. Concentrating resources, it quickly caught up with its rival.

By 1981, Novo had its own genetically modified product. Although described as 'human' insulin - a public relations masterstroke, that helped ensure its acceptance by diabetics - it was, in fact, synthetic. Today it is manufactured from yeast cells or E coli bacteria.

The insulin was put before the Medicines Control Agency, a government body which checks the safety of drugs before licensing them for sale. Novo was desperate to get its product on the market before Lilly's, and found the MCA officials extremely co-operative. 'It was cutting-edge science and very glamorous,' says Dr Laurence Gerlis, who was then Novo's director of medical research but is now an outspoken critic. 'The MCA were keen to be seen encouraging biotechnology.'

Opponents of human insulin now suggest that the MCA failed to demand sufficiently rigorous clinical trials for what was the first genetically produced drug to be licensed in Britain.

The first research using human insulin had been carried out in 1980 using just 17 people - none of them diabetic, and all of them men - and it seems that the pre-licensing trials were carried out on a group of only 300. Nowadays, trials generally involve groups of 1,000 to 1,500. But back in the 1980s, according to Dr Gerlis, standards were not so demanding. 'We just had to prove that this really was insulin,' he says. To market the new drug, Novo's intention was to employ a 'substitution strategy'. If the company could persuade its existing animal-insulin users to switch over to the human version, it could effectively clean up before Eli Lilly's launch in September 1982. The medical justification for this strategy depended on the new product having an identical effect on the human body to insulin from pigs. But when Novo's medical advisory committee met in Copenhagen in April 1982, Dr Gerlis told the marketing men the bad news: animal and human insulin were not the same.

Pork insulin is less soluble than human insulin and has different amino acids. Crucially, says Dr Gerlis, human insulin is faster and more aggressive in its effect on blood sugar levels. As far as Dr Gerlis was concerned: 'We were asking for a licence to market human insulin, not for permission to entirely replace the existing pork insulin. There is an important difference.' He and his committee advised that the substitution plan should be abandoned.

At the launch two months later, however, Novo announced that 'human insulin supersedes porcine insulin'. The company signalled its intention of gradually withdrawing pork insulin from the market.

The marketing men had over-ruled the medics - and the vast majority of British diabetics subsequently followed their consultants' advice and switched to the new product. Some were simply handed the new insulin when they presented their prescription at the pharmacy, without realising anything had changed. Most patients appeared to adapt without problems and it should be stressed that this continues to be the case. But by the mid to late Eighties, reports began to surface suggesting that a sizeable minority were suffering difficulties. They spoke of finding themselves 'operating on automatic pilot', feeling confused, tired and ill, or undergoing such severe personality changes that relatives felt they were 'no longer the same person'.
Then there were the mysterious deaths. Often the victim was young - in their teens or twenties - and living alone. They went to bed in apparently perfect health and never woke up. It was dubbed 'adult cot death' or 'dead in bed syndrome'. Such sudden tragedies had happened before among diabetics, but usually there was evidence of convulsions prior to death. With these cases the bed was entirely undisturbed. The victim had died without trauma or struggle and without apparent cause.

The stories are heartbreaking. In April of this year, l5-year-old Selina Trapp from Derby spent the evening at a friend's house and was home promptly for 9.3Opm, just as she'd promised her parents. She had supper, chatted with her mother, watched a little TV and went up to bed. She was a healthy, lively girl, whose diabetes didn't prevent her enjoying a full and active life.

She was found by her mother at just before 7 o'clock the following morning. She was lying face down on the bed, and wouldn't respond to efforts to wake her. Her father gave the kiss of life but it was too late. The verdict at the inquest was 'death due to hypoglycaemia'.

One of the youngest victims was eight-year-old Zoe Burbridge from Northampton, who died in her sleep in 1994. Her mother, Deborah, is convinced that human insulin was to blame.

It seems that in a significant minority of patients - perhaps around five per cent - human insulin blocks the body's warning signals when blood sugar levels become dangerously low. Such undetected hypos can swiftly lead to coma and death.

In normal circumstances, the diabetic is alerted to the onset of hypos (even when asleep) by sweating, shaking and feelings of faintness. These worrying signals allow the diabetic to swallow a chocolate bar or fizzy drink, replenishing their blood sugar so that all is well again. But mounting evidence suggests that in some cases genetically engineered insulin entirely masks the onset of hypos, a]lowing the patient to slip into coma without warning. Increased frequency of hypos may also cause damage to the nerves that control the heart.

By the late 1980s more than 80 per cent of British diabetics were injecting human insulin and concerns were increasing. In the space of two years, the British Diabetic Association received more than 3,000 letters of complaint. In 1990, it announced it was setting up a research project directed by Dr Natasha Posner to investigate. Dr Posner submitted her report the following year, but the BDA - which receives rough]y one third of its annual income from pharmaceutical companies - announced that it would not be publishing the findings as they were felt to be 'too alarmist'.

Substantive evidence about the safety of human insulin remains hard to come by. One Liverpool University study reported in the Lancet, which found no difference between human and anima] insulin, studied just seven patients. As Jenny Hirst of the Insulin Dependent Diabetes Trust, a patients' pressure group, points out: 'If adverse reactions occur in around five per cent of diabetic users, how do you judge five per cent of seven patients?'

Dr Laurence Gerlis, the former Novo Nordisk research director, is equally sceptical about tests purporting to give human insulin a clean bill of health. 'It is very difficult to prove a negative in clinical trials,' he says. 'The same problem comes up with the MMR vaccine. How do you prove MMR doesn't cause autism? The trouble is that the effect may be there, but your tests have failed to show it.'

This cuts both ways. In the absence of research studies, defenders of human insulin feel able to dismiss stories of harmful side- effects as mere 'anecdotal evidence'. But as Dr Gerlis explains, there is a long history of such anecdotal reports being accepted as grounds for concern. It's simply a matter of listening to the people who actually use the drug in question.

'If a drug appears to be showing adverse effects, then we take it off the market. Eli Lilly's Opren drug for arthritis is an example. But in this case we have failed to listen to what patients have told us.'

By 1991 disillusionment had set in and 400 UK diabetics joined together to take legal action against Novo Nordisk. More than 30 lawyers were involved, and strategy committees were set up in England and Scotland. Solicitor George Hann sat on the Scottish committee and was charged with responsibility for securing expert medical witnesses to support the case against human insulin. A respected legal figure and himself a diabetic, he remains astonished by what happened next.

Mr Hann wrote to over 20 diabetologists asking if they would be prepared to help. He got only one response, which was negative. Otherwise there were no replies. When he investigated, he says, he discovered that all the consultants were now receiving research grants or consultancy fees from Novo Nordisk. Although there is no suggestion of impropriety, this clearly torpedoed any chance of them giving evidence for the dissident patients. 'Novo Nordisk were very quick off the mark,' says Mr Hann. 'They had bought up every diabetologist in Scotland. Without medical opinion we couldn't take it any further. The action was effectively stymied.'

Another Edinburgh solicitor confirms this extraordinary story. 'As I recall,' he says, 'every single diabetic specialist seemed to be a paid official consultant to Novo Nordisk. That created a potential conflict of interest that prevented them from being used as witnesses. It very effectively pulled the rug from under us.'

Novo Nordisk denies any attempt to silence the consultants, but it was sufficiently troubled by the threat of litigation to have appointed a PR firm, Key communications, with a brief to 'defend the safety profile of genetically engineered human insulin'.

When the English legal action collapsed, because patients were unable to obtain legal aid, Key Communications was triumphant, 'Novo's reputation remained intact among patients, health professionals and media' the company boasted.

The rebel patients remain unconvinced. Much of the case centred on so-called ' double blind , trials -in which neither the doctors nor the patients know which type of insulin is being administered. But some diabetics who had already reacted badly to genetically engineered insulin had refused to take part, because they were so scared of its effects.

Critics also point out that one of the crucial trials, conducted at King's Hospital in London, involved just 17 patients and gave them only two months to see if they reacted badly to the new insulin [other evidence suggests adverse symptoms may appear only after a year or more]. The trial was directly funded by Novo Nordisk. The company's medical director, Dr Alan McDougall, insists that the work was totally independent. 'It doesn't mean in any way that research is biased because we funded it,' he says.

Novo's promotion of human insulin has also been aggressively supported by the British Diabetic Association. In 1996 Lawrence Gerlis and Dr Matthew Kiln - a GP and critic of human insulin - each received a letter from Professor Harry Keen of the BDA in which he accused them of 'professional misconduct' because their critical stance would frighten the majority of diabetics happy with human insulin. Dr Gerlis says both he and Dr Kiln were put under 'tremendous pressure, especially by the BDA'. In 1997, the BDA placed a number of advertisements in Sunday newspapers to denounce Dr Kiln as 'irresponsible'. 'Why,' asks Dr Gerlis, 'should a charity that raises money from patients take such a role?'

The charity, now renamed Diabetes UK, is unrepentant. It agrees that there 'was a concern' about the safety of human insulin, but insists 'there is no evidence to back it up'.

Now, however, a report from the Cochrane Collaboration - a respected organisation that reviews medical research - has attacked the 'poor methodology quality' of most of the trials. The report found that 'patient-orientated outcomes' - meaning quality of life to death rates were not investigated with sufficient rigour. It also found no proof that the new insulin was superior to its animal-based predecessors.

Concerns about the new insulin are not confined to the UK, however. Canada has recorded 121 instances of human insulin causing seizures, convulsions and extreme hypos, whilst the American Food and Drug Administration says it has received 'thousands' of similar reports.

'There are individual cases you can't explain,' concedes Dr McDougall of Novo Nordisk. 'No one knows why these young people are dying.'

As well as Novo Nordisk, which has by far the largest market share, genetically engineered insulin is now supplied in the UK by Eli Lilly and a third company, Aventis pharmaceuticals.

For the critics, the central issue is choice. Many doctors fail to inform patients that alternatives to human insulin are available, or that some diabetics seem to react badly to it. New patients are invariably put straight onto human insulin without explanation. Yet many of those who experience unpleasant side-effects report almost miraculous improvements once they switch back to pork or beef.

Shirley Stone, 59, from Hertfordshire, spent eight years suffering from 'horrendous symptoms' - palpitations, painful joints, aggression and constant fungal infections - after being switched to human insulin without consultation. The symptoms stopped 'overnight' when she returned to animal insulin.

Beverly Freeman, 31, from Northampton, underwent a similar transformation. After being put on human insulin at the age of 12, her weight ballooned to 15 stone and she suffered from constant exhaustion. 'It was like having really bad PMT three weeks a month,' she says. 'In effect, I lost my teenage years. I was so unwell that I was forced to drop out of school and my education was totally disrupted.' Switching to animal insulin at the age of 23 changed her life. 'I felt better within four weeks,' she says. She now has a degree, a family, and a job campaigning for the Insulin Dependent Diabetes Trust.

But Beverly and Shirley, like many others, are haunted by the fear of having to return to genetically engineered insulin if alternative supplies are not maintained. Although Novo Nordisk still produces a limited amount of animal insulin, the company intends to discontinue it over the next few years. The company insists it would not leave people 'high and dry', adding that 'if we withdraw animal insulin in the UK we would give a minimum 18 months' notice'. But this does little to reassure people like Beverly and Shirley.

Animal insulin is no longer on offer from Novo Nordisk in France, Germany, Belgium, Holland, Canada and Australia. Although it remains available in Britain through a small independent company, CP pharmaceuticals, there are many who fear for the future.

These fears have risen since last December, when Novo Nordisk bought up a Brazilian company called Biobras which is the world's main supplier of the raw materials needed to make animal insulin. Two months ago, Novo chairman Viggo Birch wrote to assure Jenny Hirst, of the Insulin Dependent Diabetes Trust, that 'in the short term' the company had no plans to terminate the production of animal insulin at Biobras. Developments in the 'long term', however, would 'be in line with our strategy to discontinue production of unmodified animal insulin'.

'There are a lot of people living in fear of animal insulin being withdrawn,' says Shirley Stone. 'If it is, they're going to be in terrible trouble.'

Once again, it seems, the voice of the patient is going unheard.