Miracle cure, or mere illusion?

There's a snag with the media's favourite answer to humanity's most stubborn diseases. So far, gene therapy doesn't work. Tom Wilkie reports

Carly Todd, Britain's first gene therapy patient, recently celebrated her third birthday. Two years ago, she made front-page headlines. Doctors were going to correct an inherited defect in her immune system by genetically engineering some of the cells in her body.

It was the ultimate in high-technology medicine, combining the human interest of a baby at risk with the icon of post-war science, the double helix of DNA. One of the oldest and most firmly fixed facts of human existence - that our genetic constitution is given to us and is unalterable and inescapable - was to fall to the inexorable advance of scientific progress.

Carly had inherited defective genes from her parents. This meant her immune system was unable to produce a vital protein, leaving her vulnerable to infections - even those which, for the rest of us, would cause no more than a sniffle. The condition was similar to that of the famous case in Texas of the "boy in the bubble" who had to be kept in a germ-free environment to protect him from the chance of infection even by his parents - a story later turned into a Hollywood film starring a young John Travolta. Gene therapy offered hope of a permanent cure for this rare but devastating condition. Carly's parents had already lost a son to the disease, only days before she was born. By transplanting "correct" genes into the cells of her bone marrow, doctors hoped that these cells would be able to make the vital protein and so create a functioning immune system.

But it didn't work. A year after the operation, Carly's doctors were unable to find any trace of the corrected genes in her bone marrow cells. She is alive and reasonably well now thanks to more conventional treatment: she receives the protein in the form of regular injections, costing around pounds 1,000 each.

After the high expectations, enthusiasm is waning. "No human disease has been cured by human gene transfer and it is not clear when this will be accomplished," according to a review of human gene therapy published last week in the American journal Science. "All of the human gene transfer studies have been plagued with inconsistent results," the article continued.

Despite this, gene therapy is already big business. According to research from the Science Policy Research Unit at Sussex University, more than 100 clinical trials are under way or about to start in the United States alone. And the work, in the US at least, is being driven in part by commercial considerations. Stock market investors have stumped up around $1bn to set up some 20 dedicated gene therapy companies, ready to cash in on what is seen as a potentially lucrative new sector of the health-care business.

The European Commission is worried that Europe, with only four gene therapy companies, may be missing out on a lucrative medical market. Most of the experimental work on gene therapy is still being carried out by public sector bodies, such as universities and the NHS, often funded by charity. Next month the Commission is starting a project to assess how to develop a strong European gene therapy industry.

But so far there has been more hype than substance. Carly Todd's gene therapy followed the pioneering case of Ashanti DeSilva, a little girl with the same condition as Carly and who made history in 1990 when, at the age of four, she became the world's first authorised gene therapy patient. In the American tradition, Ashanti last year testified to the US Congress on the success of her gene transplant, prompting George Brown, then chairman of the House of Representatives Science Committee to describe her as "living proof that a miracle has occurred".

Yet it is not clear whether Ashanti, any more than Carly Todd, has benefited from her gene therapy. The work has not been written up and published in the scientific literature and it is impossible to establish if she is alive and well today because of the gene therapy or because she, too, has been continuing to receive conventional injections of the missing protein.

In Britain, the hype has been less intense, but gene therapy has entered the public consciousness as if it were an established fact rather than a yet-to-be-proven possibility. In the past three months alone, media accounts have cited gene therapy in connection with the crippled Superman actor, Christopher Reeve, as a possible way of getting nerve cells to regrow (there is no work in humans along these lines); as a "best hope" for the Aberdeen footballer Brian Irvine who has developed multiple sclerosis (again, there are no protocols for gene therapy as an answer to this condition); as a cure for baldness; and to deal with cancer.

Internationally, Britain is the leading gene therapy nation behind the Americans. By the beginning of October, 44 patients in Britain had received gene transplants and a total of 12 applications to conduct gene therapy trials had been approved by the Government's Gene Therapy Advisory Committee (GTAC). Not all these have yet been carried out. Although inherited diseases were expected to be the main target for this therapy, the focus of most applications is cancer. However, very few cancers are inherited, most arise instead from genetic damage sustained during adult life.

Cancers and HIV are among the targets for Britain's leading gene therapy company, Therexsys. The company, founded in 1992 and based at Keele University Science Park, hopes to commence clinical trials of its HIV therapy next year. It has already succeeded in raising pounds 6.4m and next month will begin a second round of financing. "We see genes as medicines," says Dr Roger Craig, its chief scientific officer. "You have to deliver to the right target cell and you have to control the potency of the medicine. You also have to manufacture at scale." There will be no shortage of genes to use, Dr Craig says. "The issue becomes: how do you wrap up your DNA so that it will be taken into cells?".

As Dr Craig indicates, the most fundamental aspect of gene therapy - getting the new gene inside the cells where it is supposed to substitute for the patient's own damaged or defective genes - is proving to be the most difficult. Carly Todd's doctors deliberately infected cells taken from her bone marrow with a virus of a type known to infiltrate its genes into human DNA. The researchers used genetic engineering to get the human gene into the virus and to ensure that the virus was no longer pathogenic. But although the virus ought to have been a perfect vehicle to carry the genes inside her cells, her gene transplant failed to "take".

A few months later, researchers at the Royal Brompton Hospital in London used fatty globules, known as liposomes, to carry the genes into the airways of their patients suffering from the inherited lung disease cystic fibrosis. The idea was that the fatty membrane of the liposome would unite with that of the patients' cells, thus enabling the genes to get inside the cells and do their therapeutic work. But the researchers found that they could get the genes into the cells in only five out of nine patients and that the effect lasted only about a week.

Dr Craig believes that Therexsys can target tissues and organs precisely with its "virus-like particle" technology. It is, he says, "quite a novel solution". Moreover, Therexsys has a second piece of technology which he believes will allow it to control the expression of the gene once it is in the tissue. But the gene therapy unit that the Cancer Research Campaign hopes to set up at the Beatson Cancer Research Institute in Glasgow will take a very different approach. Instead of trying to target tumour tissue, researchers there intend to flood all the cells in the body with a tumour suppressor gene that will be harmless in normal tissue but which will persuade cancerous cells to commit suicide.

The two approaches are radically different yet are supposed to achieve the same thing. Their inconsistency suggests that something pretty basic is lacking from current techniques. Yet in the US, those investors will soon start demanding a return on their money, piling on commercial pressure for more widespread use of gene therapy.

Other major pharmaceutical companies - even those most aggressively pursuing genetics - are sceptical about the potential of gene therapy. "We have no investigations going on and no intention of being involved in gene therapy in the future," Dr George Poste, chairman of Pharmaceuticals Research for SmithKline Beecham says. "There is not one tabulated example of efficacy of gene therapy in one patient."

The techniques have not been properly regulated in the US, he continues. "There has been close to an abdication of regulatory oversight in the US", consequent on "the hype that goes with it". Researchers have been allowed to carry out "saturation bombing" of patients' DNA without regard to the possibility that the genes might insert in the wrong place and disrupt intact genes - which could cause tumours. As in Britain the focus for gene therapy has been on the terminal stages of fatal diseases, such as Aids and cancer. Only "when that shifts to less threatening diseases, then the regulatory agencies will toughen it up", Dr Poste says.

Although Department of Health officials believe there has been less hype in Britain than in the US, the Government's regulator, GTAC, has warned that "Many of these gene therapy research trials are unlikely to benefit individual patients significantly and the importance of communicating the value of such trials while not raising false hopes in patients and their families, no matter how well meant, is a special challenge".

In his recent book, Science and the Quiet Art, Sir David Weatherall, regius professor of medicine at Oxford University and one of the world's leading experts on human genetic disease, notes that it can take decades for scientific discoveries to leave the laboratory and enter the hospital clinics as proven and effective therapies. Some researchers fear that if the public becomes disenchanted with gene therapy because of false expectations that cannot be fulfilled, this may spill over into antagonism against the more limited but still useful things that modern genetics can achieve.

In July, the House of Commons Select Committee on Science and Technology published the results of a major investigation into the science of human genetics. Gene therapy occupied only 19 out of 289 paragraphs of the report. More important than therapeutics, as far as the committee was concerned, was the diagnostic potential of modern genetics. It recommended that there should be a regulatory body to monitor genetic testing. But public policy has hitherto been driven by the popular mystique of gene therapy, which led to the formation two years ago of a gene therapy advisory committee . In contrast, the Government has yet to respond to the Select Committee's proposals on gene testing.

Early next year, at the Royal Brompton Hospital in London, researchers will start the second phase of their gene therapy for cystic fibrosis. The doctor in charge, Duncan Geddes, is a model of cautious, professional propriety: "Progress is slower than some people thought. Everybody is confident that it will come right, but it will be in years not months. We're testing safety and gene transfer. Nobody's at the stage yet of trying to make people better."