The Rise and Fall of Modern Medicine (42 page)

Those unfortunate enough to be born into families where
several relatives have died young from such diseases naturally want to know what they can do to avoid a similar fate. There are two obvious benefits from a genetic test. Those found to be ‘negative', that is, who do not carry the mutant gene, can relax, reassured that their risk of these illnesses is no greater than that of the general population. Those who are found to carry the mutation can take pre-emptive action, either by having regular screening tests, such as mammographies to detect breast cancer early, or indeed submit voluntarily to bilateral mastectomy, followed by reconstruction of the breast with an implant, in an attempt to entirely rid the body of any threat of malignancy from this source.
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The gene hunters, following their success in finding the genes for the commoner genetic disorders such as cystic fibrosis, subsequently turned their attention to finding in a similar way the genes that predispose to cancers that run in families. In 1994 the first breast cancer gene, named BRCA1, generated the usual excitement and speculation associated with every genetic breakthrough. This was followed eighteen months later by the discovery of a second gene, BRCA2. These two breast cancer genes are believed to account for most ‘hereditary' cases of the disease, but they are normal in, and therefore uninformative about, those cases that are non-hereditary and make up 95 per cent of the total. Further, as with all genetic diseases, many different mutations of the genes involved have been found, which, as can be imagined, makes the problem of testing considerably more complex.
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This leads to the central issue of genetic testing for these common diseases: had the gene for ‘hereditary' breast cancer also been involved in the remaining 95 per cent of cases, one could imagine that perhaps, at some time in the future, it might be possible by genetic testing to predict the probability for any
individual of their subsequent risk of developing this type of serious disease in later life. But clearly this is not going to be the case. It may indeed be useful in the minority whose cancers run in families, as it will be useful to know whether the abnormal gene is or is not present. But widespread genetic testing is scarcely an option, not least because it would be foolhardy to volunteer for such tests – the results could seriously and adversely influence the chances of obtaining life insurance, or would so increase the premiums for private health insurance as to make them unaffordable.
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In summary then, back in the early 1980s it was quite legitimate to assume that the discovery of the genes involved in disease would, almost by definition, considerably widen the scope of medicine to include the prevention of ‘common' genetic diseases, such as cystic fibrosis, while deepening scientific knowledge of the genetic contribution to adult diseases in a way that would allow them to be averted or ameliorated. Both goals seem now more unachievable than ever, a curious paradox that will be explained after an examination of the final of the three great promises of The New Genetics: gene therapy.

The supreme aspiration of The New Genetics – taking the technical innovations already discussed to their ultimate logical conclusion – is gene therapy: the correction of genetic defects by physically changing the genes themselves.

The immediate prospects for gene therapy lie in the treatment of the same group of diseases caused by a defect in a single gene, most notably cystic fibrosis and Duchenne's muscular dystrophy (DMD). Indeed much of the attraction of gene therapy is that it offers a positive alternative to the eugenicist ideology that is implicit in genetic screening. How much better it would be to be able to correct the genetic defect in a child with, for example, cystic fibrosis rather than selectively aborting those foetuses found to be carrying the abormal gene!

But how to do it? First, the gene responsible for those diseases that might be suitable for gene therapy must be known and, as we have seen, molecular biologists have been very successful at locating several of them. Next, a copy of the ‘normal' gene must somehow be introduced into the abnormally functioning cell, which in children with cystic fibrosis, for example, means the normal gene must be inserted into the millions of cells lining the airways, which are the ones adversely affected by the disease. The most obvious candidate to act as a ‘vector' to carry the normal version of the gene into the abnormally functioning cell is a virus, as it has both the capacity to penetrate the cell wall and, crucially, integrates its own genes into that of the host cell's DNA. Clearly, if a virus is to act as a vector it must first be ‘disabled', by removing those of its genes that have the potential to
damage the cells they invade, and then ‘modified', so as to include the normal human gene. The normal gene, it is to be hoped, once incorporated into the genome of the defective cell, will override the action of the abnormal gene and thus restore the cell's functioning to normal. It all sounds – and indeed is – an astonishing piece of science.

The first gene therapy experiment took place in 1990 at the US National Institute of Cancer in Washington, DC. Two girls, nine-year-old Cynthia Cutshall and four-year-old Ashanthi de Silva, were both victims of a very rare genetic disease known as ADA deficiency due to a defect in the gene needed for the proper functioning of the body's immune response. The ADA enzyme (adenosine deaminase) in the white blood cells or ‘T lymphocytes' is reduced to a critically low level, with similar effects to those of AIDS, leading to repeated devastating infections. This ever-present threat means those affected with the disease have to live their terrible and abbreviated lives in a plastic bubble isolated from the external world. Their prospects improved markedly following the development of a special preparation of the ADA enzyme that could be directly injected into the veins, thus restoring the competency of the T lymphocytes, but this treatment, at £100,000 a year, is very expensive. It would seem a better and certainly more elegant solution to correct the underlying genetic defect so that the T lymphocytes themselves would start making the ADA enzyme in sufficient amounts.

The more seriously affected of the two children, Ashanthi de Silva, was the first to be treated. On 14 September 1990 her white blood cells, including the T lymphocytes, were removed and exposed to the ‘disabled' virus bearing the inserted normal ADA gene. The T cells, now hopefully healthily complete with the normal ADA gene, were then reinfused back into the vein.
The entire undertaking was clinically uneventful, and thus began human gene therapy. Four months later it was the turn of Cynthia.

This first foray into gene therapy, albeit for an extremely rare condition, showed that the principles were sound. It was undoubtedly a very impressive technical achievement. Nonetheless, it was certainly not a permanent cure, as the T lymphocytes' lifespan is limited to a few months before being destroyed and replaced by others. Hence the gene therapy had to be repeated several times a year, which naturally makes it very costly. Further, both Ashanthi and Cynthia continue to receive preparations of the ADA enzyme, so it is not possible to discern the specific contribution (if any) of the gene therapy in protecting them against infection and ensuring their continued good health.
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Still, the experiment was a start, generating great excitement, as would be expected for any new, elegant, sophisticated form of treatment for a previously intractable disease, but this time with the twist – which put the news on the front page – that for the first time doctors had intervened to change an individual's genetic inheritance. Proposals for further gene therapy experiments multiplied, both for comparable simple gene disorders like cystic fibrosis and Duchenne's muscular dystrophy and for certain types of advanced cancer. ‘The concept and techniques of gene therapy have moved from being fanciful to the beginnings of human clinical application,' observed one of its pioneers, Theodore Friedmann of the University of Southern California, a sentiment echoed by Dr French Anderson of the National Institutes of Health, who had participated in the ADA experiment: ‘Human gene therapy has progressed from speculation to reality in a short time . . . the many clever applications of gene transfer that investigators are discussing ensure that gene therapy will be applied to a broad range of diseases over the next
several years,' he observed in the journal
Science
in 1992, though noting that ‘only thousands not millions of patients are treatable by current techniques'.
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Even this relatively modest expectation of treating ‘thousands' has turned out to be hopelessly optimistic. In 1995, just three years after Dr Anderson's prediction, an internal review conducted by the National Institutes of Health concluded that gene therapy was not only expensive but useless. At the time the NIH was spending $200 million a year on research into gene therapy, a sum multiplied several times over by commercial firms as investors had poured hundreds of millions of dollars into gene therapy companies in anticipation of ‘blockbuster' discoveries. Yet the two authors of the internal review found that ‘despite anecdotal evidence of success clinical efficacy has not been definitively described . . . significant problems remain in all basic aspects of gene therapy'.
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What had gone wrong? Three months before this review, the credibility of gene therapy had been undermined by two papers published in the same edition of the
New England Journal of Medicine
, both of which concluded it simply did not work.

The first paper described the results of gene therapy in twelve children with cystic fibrosis.
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The defective gene in CF results in an abnormal protein in the cells lining the airways, which produces an abnormally sticky mucus that predisposes to repeated chest infections, over time damaging the lung irreparably. To correct this genetic abnormality, each child had a solution instilled in the nose containing millions of modified viruses containing the normal gene. These viruses would, it was hoped, infect the cells lining the airways and thus replace the abnormal gene with a normal one.

The second paper described the results of gene therapy in twelve children with muscular dystrophy, in whom a defective
gene leads to the production of an abnormal muscle protein so that, from the age of four onwards, they become gradually weaker. By the age of ten most are wheelchair-bound.
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The twelve children in this study were given injections of primitive muscle cells containing the normal gene directly into the muscles of one arm.

Neither experiment worked. In the first, an analysis of the cells removed from the nose showed that in only one of the twelve children was there any evidence of transfer of the normal gene, whose effects did not last long and were insufficient to correct the underlying defect. As for the twelve boys in the muscular dystrophy experiment: ‘There was no improvement in the strength of the muscles that received the injection in any of the patients.' Dr Jeffrey Leiden of the University of Chicago, in an accompanying editorial commenting on these two experiments, observed how far the results fell short of the goal of ‘successful gene therapy', which would require for both conditions ‘the delivery and long-term expression of the appropriate genes in large numbers of cells throughout [damaged] tissue'.
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The main impediment to success would seem to be ‘the vector' – the virus is just not very good at getting the normal gene into the diseased cell – but the problem is actually much more serious. The logic of gene therapy presupposes that the 25,000 or so genes in the cell work independently of each other, so that a faulty gene can be replaced, in a similar way to replacing a faulty car part. But for every gene that codes for a protein, there are others that regulate its actions and yet others that regulate the regulators. The genome can thus be compared to an orchestra, which must produce multiple musical notes in harmony to generate the desired effect. Just as one cannot correct a poor performance of a Beethoven symphony by
changing a single note, so one cannot repair a disease like cystic fibrosis just by inserting a copy of a normal gene without also linking it up to all the other genes that regulate it.

The gene therapists put a brave face on the NIH report, admitting its therapeutic potential had, as Theodore Friedmann put it, ‘possibly become greatly exaggerated and that hopes for clinical success had become confused with fact . . . We all conveyed advances in an unrealistically rosy way . . . [with] undeliverable promises.' These were, however, still early days: ‘Gene therapy is not a failure, it is simply still too immature to deliver yet on its promises.'
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Perhaps, but within a few months of the NIH internal review
Nature
reported ‘the regular stream of proposals for innovative gene therapy experiments has dried up'.
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The New Genetics, in the three distinct but overlapping applications of genetic engineering, genetic screening and gene therapy, generates genuinely novel and brilliant answers to fundamental problems. And yet for all the enthusiasm and excitement and the millions of hours of research endeavour and the tens of thousands of scientific papers and the acres of newspaper coverage, its practical benefits are scarcely detectable. Genetic engineering has turned out to be an expensive method for making drugs that were either – like insulin – already available, or have been shown to be of marginal therapeutic benefit. Genetic screening has had hardly any impact on the prevention of the common inherited disorders, and gene therapy simply does not work. Nor, indeed, is this all, for several other much anticipated benefits of The New Genetics have similarly failed to fulfil the expectations held out for them, most notably the genetic transformation of pigs as a source of organs for transplantation.
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