THALIDOMIDE:GOOD OR EVIL?

Last month it was claimed that thalidomide has caused inheritable damage. But for some, it is now seen as a saviour. Hilary Bower reports on both sides of the argument

Images of the original effects of thalidomide are seared into the British psyche. Launched as a magic bullet sedative and a safe cure for morning sickness in 1958, thalidomide became one of the worst nightmares of modern medicine as thousands of children were born in 1959, 1960 and 1961 with flippers in place of limbs and internal defects. In all, there were an estimated 12,000 damaged babies worldwide. This was horror and heartbreak the like of which the pharmaceutical industry had never seen, a tragedy which some are now suggesting is being passed down the generations.

In this summer's issue of the clinical research journal Teratogenesis, Mutagenesis and Carcinogenesis, Dr William McBride reports work supporting his controversial contention that thalidomide is the first pharmaceutical drug to cause inheritable damage - a claim that raises strong emotions across the medical community. An Australian obstetrician who was one of the first to sound the alert over thalidomide in the 1960s, Dr McBride has devoted much of his career to investigating the thalidomide tragedy, but his reputation was tainted after he was found to have falsified data in another research project, and he was struck off the Australian medical register in 1993.

McBride's hypothesis is that thalidomide harms the development of germ cells (the forerunners of sperm and eggs) in foetal life by causing double strands of DNA to break and create abnormal single-strand cells. When the foetus is unable to repair such breaks, some germ cells carrying the abnormality are passed on through sperm and eggs to future generations, he maintains. According to McBride's claims, thalidomide could be causing the symptoms in the grandchildren of mothers who used thalidomide when it was first introduced in the late Fifties.

In rats, McBride says he and colleagues have observed thalidomide bonding and changing DNA in cells. So too, he claims, have Californian scientists who are due to report on work on rabbits. "Thalidomide definitely binds to the DNA in two species. No more scientific work needs to be done to show this. It's now up to the Department of Health to do a clinical follow- up study of thalidomide victims and their children." Of approximately 500 children born to British thalidomide victims, 10 have limb malformations of a similar type. The expected incidence of limb reduction deficits is one in 1,500 births, says McBride, who in a visit to Britain last month, says he saw four children of thalidomide victims whose deformities he is convinced are linked to the drug's effect on their parents.

One, Georgina Harrison, the three-year-old daughter of Thalidomide Action Group deputy chairman Glen Harrison, has shortened legs and arms and only two fingers on each hand - disabilities identical to her father's.

Glen Harrison says: "I'm one of nine children, my mother was one of eight and my father one of four - I'm the only one with a disability and now my daughter has exactly the same. I've spent all my own personal compensation money fighting this, but have been told I'm scare-mongering. This is history repeating itself. How many more babies have to be born like Georgina before the Government will take action?

"We should be concerned by these findings because thalidomide is now being used for other conditions, yet we still don't know the full extent of the damage it can do."

For Harrison and other thalidomide parents, getting to the bottom of this issue is not just a matter of scientific truth. If thalidomide is a mutagen, they say, not only must thalidomide victims be warned about the risks of bearing children, but the children of victims who have "inherited" their parent's deformities must be compensated. The irony is that if the reverse is true and thalidomide is not mutagenic, thalidomide parents could themselves be victims of random genetic abnormality - and have received unwarranted compensation.

But while the Thalidomide Action Group and McBride believe the only way to find out for sure is for the Government to carry out an in-depth study of thalidomide survivors and their families, opponents say there is overwhelming scientific evidence that thalidomide cannot jump generations.

Firstly, says Dr John McLachlan, senior lecturer at the University of St Andrews School of Biomedical Sciences, and author of the textbook Medical Embryology, thalidomide would have to work in a different way than current understanding of teratogens (an agent that causes congenital malformation) and mutagens suggests, to cause birth defects to be repeated across the generation barrier.

"An agent would have to have the ability to cause a particular abnormality in one generation and, simultaneously, alter the genome in such a way that it would cause the same abnormality in the second generation. But teratogenicity and mutagenicity are two separate mechanisms - things which cause individual abnormalities during the course of foetal development need not affect the genes, and things that affect the genes are unlikely to bring about an immediate effect on the course of development."

People tend to underestimate how common congenital abnormalities are, says McLachlan. "The truth is that about one child in 40 will have a developmental abnormality detectable at birth, and, of these, limb abnormalities are the most common kind. It is possible that some of the individuals compensated as thalidomide victims were not in fact victims of the drug, but were part of the general population incidence of heritable congenital abnormality which one would expect to reappear in the next generation."

Even more compelling evidence to back thalidomide's DNA safety comes this autumn with the publication of a huge report in Mutation Research. Compiled by Professor John Ashby, a genetic toxicologist for the pharmaceutical firm Zeneca, it analyses the results of 30-odd live and test tube assays carried out by an international team of collaborating scientists from the UK, US and Holland. Test organisms ranged from human and foetal cells to rat, hamster, mouse, rabbit, drosophila, grasshopper and salmonella.

The results, says Ashby, were uniformly negative: "We have tried every possible assay and found no evidence that thalidomide is a mutagen. If anyone can think of any other ways to test it, I'd be pleased to hear from them because I can't think of any. McBride is simply wrong - he's putting up one unreliable assay against all these studies and in doing so he is implying that thalidomide is the first human germ cell mutagen.

"Chemicals don't go in and target one gene, they hit all of them. The idea that thalidomide is going to go in and target the genes that affect limb development out of the hundreds of thousands in the cell, and nothing else, is rank nonsense."

Ashby admits that of all reports ever published on thalidomide DNA activity, about half found evidence of mutagenicity. "But those experiments were conducted about 20 years ago when the assays used and the standards of data reporting were different to those considered necessary today."

Ironically, the fact that this number of assays and this standard of testing can be carried out on a drug is a direct consequence of the thalidomide disaster which changed the face of drug research and triggered the host of protective regulations that govern drug development today.

It is even more paradoxical that the name associated with such heartbreak has been transformed into a tool of hope and health. Now, almost 30 years after the catastrophe that scarred a generation, clinicians are again cautiously hailing thalidomide as a wonder drug with an ability to alleviate pain and suffering in diseases such as HIV, rheumatoid arthritis, multiple sclerosis, tuberculosis, psoriasis and cancer. The abhorred novel drug would have vanished without trace had it not been for the chance observation in an Israeli leprosy clinic. In 1965, a clinician noted that the skin lesions of a patient with intractable leprosy, who had been given thalidomide as a sedative, improved dramatically within 12 hours of taking the drug.

What makes thalidomide such a potent teratogen is still not fully understood. But what is known is that it has another powerful quality - it suppresses the body's production of tumour necrosis factor (TNF). TNF is an immune system activator crucial in our defence against infection and inflammation. But it is a double-edged sword: when TNF is working right, it is invaluable; when it's out of whack - working too long or at too high a level - it marauds through the body wreaking all kinds of damage.

Over-production of TNF has been linked to previously unexplained inflammatory conditions such as rheumatoid arthritis, multiple sclerosis, septic shock, leprosy and tuberculosis. People with advanced Aids have TNF roaring through their systems, and it's TNF that appears to be behind the chronic ulceration of the throat and mouth (known as aphthous ulcers), diarrhoea and fatal weight loss and wasting associated with HIV and Aids.

The out-of-control immune warrior also appears to speed up replication of HIV virus cells and levels of TNF in a patient have been directly linked to how rapidly an infected individual progresses to full- blown Aids. It is possible, say some specialists, that reducing the TNF could win doctors valuable time to treat the virus. Importantly, thalidomide appears to stop TNF being produced without impairing the rest of the immune system.

"Thalidomide is my miracle drug," says Ann Shippey, one of the estimated 400 patients currently taking the drug, "Without it, life would be awful. I've been on it for 10 years and I hope I can stay on it for the rest of my life."

Ann Shippey has Behcet's Syndrome - a condition which causes severe ulceration of the mucous membranes. Such membranes are in your eyes, mouth, nose, throat, lungs, bowel, urinary tract and vagina. The ulceration causes intense pain and discomfort as well as preventing sufferers from eating, drinking and generally living a normal life.

Ann Shippey first experienced this agonising ulceration at 15. Six years later, doctors diagnosed Behcet's, and for the next 15 years she, and they, tried a multitude of therapies with little result. She managed as best she could, taking up temping so as to be able to work when she could and hide in pain when she couldn't.

Ten years ago, she was prescribed thalidomide: "It put me completely into remission, it changed my life. I've been in permanent work ever since."

The number of people taking thalidomide in Britain has grown 10-fold in the past five years. Strict guidelines have been developed for its use: patients should be under close consultant supervision and must agree not to conceive while on the therapy. They are also supposed to be rigorously monitored for signs of peripheral neuropathy - the potentially irreversible nerve damage that is the major side-effect outside of birth defects, and which studies suggest may eventually affect one in 10 patients taking the drug over long periods.

But not everyone is ready to rehabilitate thalidomide. There are two overriding concerns, according to Freddy Astbury, chairman of the Thalido- mide Action Group. Firstly, despite its history there is evidence that Government's guidelines on thalidomide are not being strictly followed.

"Patients are supposed to be checked every six months for nerve damage but we've been contacted by one women who had not been checked for seven years, nor had her children who are also on the drug for Behcet's - and she has now developed peripheral neuropathy."

Some specialists counter that techniques for testing the onset of peripheral neuropathy are complex and unreliable. And new regimes for doses in recent years have also reduced to a fraction the amount of thalidomide taken, and consequently the risk of peripheral neuropathy. But Asprey puts lax monitoring down to lack of resources, lack of in-depth knowledge and a growing laissez-faire attitude towards the drug: "This is a very dangerous drug. If it's got to be used then it has to be used safely. Government guidelines must be taken seriously, but they are voluntary and there is nothing to make a doctor follow them."

Nonetheless, thalidomide is seen to offer sufficiently unique treatment that research is intensifying into possible uses. In Britain, immunologists from the Queen's Medical Centre, Nottingham who gave thalidomide to 59 patients with persistent, incurable oral and genital ulceration caused by a variety of conditions including Behcet's Syndrome, found 80 per cent went into complete remission within a month of starting therapy. One in five patients were then able to stop treatment while the others had to continue taking a low dose to keep their condition in remission.

In another study, specialists at St Thomas's Hospital in London found eight of 16 patients, whose incurable skin disease caused by the auto immune condition lupus erythematosus had outwitted every other drug treatment, went into near or complete remission on thalidomide, while a further 40 per cent gained partial remission. And both groups could be maintained in health on half the initial dose. Similar findings have also been published in the United States.

Thalidomide is also effective against the chronic wasting, known as cachexia, suffered by both cancer and Aids victims and also those who contract graft versus host disease, the chronic rejection state that can be a deadly complication of bone marrow transplantation as treatment for leukaemia. These patient groups again show high levels of TNF. Studies in both America and Britain show that thalidomide halts the wasting process and patients begin to regain weight.

Thalidomide is also being hailed as an anti- cancer drug because TNF, it has been recently discovered, plays a role in stimulating angiogenesis - the growth of new blood vessels - which is crucial to the growth of tumours. Thalidomide appears to inhibit this growth, literally starving the tumours of their life blood.

In June this year, American researchers from the National Institutes of Health Clinical Center in Bethesda, Maryland reported that the tumours of patients with prostate cancer stabilised with thalidomide treatment and levels of prostate-specific antigen - the chemical marker that signals malignant activity - went down. The researchers also reported positive trends in ongoing trials using thalidomide against brain tumours, breast cancer and Karposi's sarcoma.

Controlling new blood vessel growth may not only help in cancer, but could also have positive effects in diseases such as elderly eye degeneration and diabetic eye complications, in which new vessels grow across the eye.

And it is this action of preventing blood vessel growth which, when it occurred during a crucial window in foetal development, is thought to have obstructed the normal growth of limbs in the children of the Sixties.

Angus Dalgleish, professor of oncology at St George's Hospital London, has been conducting trials of thalidomide in cancer and HIV patients for more than two years, and this year hopes to see two analogs of the original drug created by US firm Celgene go into clinical trials.

"Thalidomide is one of the most exciting drugs we've ever worked with because it potentially has a major role in several major diseases. Out of a chaos of pathology, it has highlighted a common pathway that is quite astonishing. Thalidomide analogs won't necessarily be a cure but they may be a major controlling therapy that could change people's lives. You can take someone whose mouth is ravaged by ulcers, give them steroids, cyclosporin and nothing happens, but give them just one tablet of thalidomide and the next morning they will be drinking and eating. We had people who've had chronic diarrhoea for over a year which just stops with thalidomide. Patients think it is magic stuff."

Although it was seen that way in 1958 as well, now more is known about the drug and its side- effects, doctors are more willing to consider its use.

The major patient complaint about thalidomide has been that it makes them incredibly sleepy, says Dalgleish, not surprisingly, as the original was marketed as a sedative. But patients with advanced Aids symptoms - such as non-stop diarrhoea - for whom sleepiness was a small price to pay for relief, found this side- effect wore off as they persisted with the drug. This, again, is unsurprising since one of the reasons that thalidomide was not a good sedative was because the body becomes quickly accustomed to it.

Professor Dalgleish stresses all trial work using the original drug has been done in patients who could not possibly be pregnant and the aim, says Dalgleish, is to find analog compounds based on thalidomide which have neither the sedative nor the teratogenic effect of the original, but which retain its ability to knock down TNF. So far four "families" of analogs have been developed. If they prove effective, says Dalgleish, they could be the "blockbuster" drugs of the future with efficacy across diverse diseases."

Behcet Syndrome Society, 3 Church Close, Lambourn, Hungerford, Berks RG17 8PU. Tel 01488 71116.

THALIDOMIDE YEARS

EARLY FIFTIES: Thalidomide fails as an anti-epileptic drug in animals, but is found to produce major drowsiness.

1958: It is launched as a sedative and a safe cure for morning sickness in Europe and Australia.

1959-61: Children are born with flippers in place of limbs and internal defects. There are an estimated 12,000 damaged babies worldwide.

1961: Dr William McBride writes to The Lancet, following observations in his Sydney practice of pregnant women who have taken thalidomide. It is regarded as the first public warning that the drug could cause deformities in babies.

1962: Thalidomide is withdrawn.

1967: Reports on the nature of thalidomide damage show that the effects occurred when mothers took it between 35th and 50th day of pregnancy.

1965: A doctor at an Israeli leprosy clinic observes that the skin lesions of a patient with intractable leprosy, given thalidomide as a sedative, improve dramatically within 12 hours of taking the drug.

1984: Limited use of thalidomide on a named patient basis only is approved.

1993: McBride is struck off the Australian medical register, found guilty of scientific fraud over experiments with anti-morning sickness drug, Debendox.

August 1997: In the research journal Teratogen-esis, Mutagenesis and Carcinogenesis, McBride reports work supporting his contention that thalidomide is the first pharmaceutical drug to cause inheritable damage.

October 1997: Report of 30-plus assays on thalidomide published in the research journal Mut-ation Research shows no evidence of mutagenicity.